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Blanketing effect Astronomical metals, which produce most of a star's spectral absorption lines, absorb a fraction of the star's radiant energy (a phenomenon known as the "blocking effect") and then re-emit it at a lower frequency as part of the "backwarming" effect. The combination of both these effects results in the position of stars in a color-color diagram to shift towards redder areas as the proportion of "metals" in them increases. The blanketing effect is thus highly dependent on the metallicity index of a star, which indicates the fraction of elements other than hydrogen and helium that compose it. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36197961 | Blanketing effect |
Conversion electron Mössbauer spectroscopy (CEMS) is a Mössbauer spectroscopy technique based on conversion electron. The CEM spectrum can be obtained either by collecting essentially all the electrons leaving the surface (integral technique), or by selecting the ones in a given energy range by means of a beta ray spectrometer (differential or depth selective CEMS). This method allows the use of simple and inexpensive detecting equipment, mainly flow-type proportional detectors in which large counting rates can be obtained. This last characteristic makes possible the study of samples with the natural abundance of the Mössbauer isotope | Natural_sciences | https://en.wikipedia.org/wiki?curid=36216090 | Conversion electron Mössbauer spectroscopy |
Conversion electron Mössbauer spectroscopy The information furnished by the integral measurements can be increased by using various angles of incidence or by depositing thin layers of inert material on the sample. In the energy range used in CEMS, the incident radiation can interact with the absorber through two kinds of processes: (a) conventional interactions – photoelectric and Compton effects, and (b) nuclear resonant absorption – Mössbauer effect. Due to conventional interactions the beam is attenuated and electrons are emitted from the sample. The nuclear de-excitation following the resonant absorption takes place by emission of either a gamma ray or an internal conversion (IC) electron | Natural_sciences | https://en.wikipedia.org/wiki?curid=36216090 | Conversion electron Mössbauer spectroscopy |
Conversion electron Mössbauer spectroscopy In the latter case, the atom is left in an ‘excited’ state with a hole in an inner shell; the energy excess is given away with emission of Auger electrons and/or X-rays. Thus, the electrons emitted from the sample as a consequence of the Mössbauer absorptions are: (a) primary (IC or Auger) electrons originated in the de-excitations of the nuclei excited by the incident beam, and (b) secondary electrons originated by conventional interactions of photons (or resonant absorption of gamma rays) emitted after resonant absorptions. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36216090 | Conversion electron Mössbauer spectroscopy |
Beni Abbes Museum also known as (Béni Abbès Museum) () is an art museum located in oasis town of Beni Abbes, Béchar Province, Algeria. It is "a resource dedicated to desert fauna, fossils and Algerian arts and crafts." Béni Abbès Museum is popular in Algeria. It is supported by the Saharan Research Center. The museum houses displays desert fauna, fossils and traditional arts and crafts, such as carpets, wall hangings, ceramic items, woodcarvings and jewelry. The museum, which is supported by the Saharan Research Center, displays an extensive range of different types of dates. Dates are one of the mainstay crops of oasis towns and villages in Algeria. The oasis of Beni Abbes has its own myth | Natural_sciences | https://en.wikipedia.org/wiki?curid=36231456 | Beni Abbes Museum |
Beni Abbes Museum Local people claim that: The town of Beni Abbès is a popular tourist destination and the museum provides insights into its history and culture. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36231456 | Beni Abbes Museum |
Meta-operator In theoretical physics, the word meta-operator is sometimes used to refer to a specific operation over a combination of operators, as in the example of path-ordering. A meta-operator is different from an operator in that it does not correspond to a linear transform in the Hilbert space. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36235324 | Meta-operator |
Yao Tandong (; born July 1954 in Gansu) is a Chinese glaciologist, a member of the Chinese Academy of Sciences (CAS). He served as Director of the CAS Institute of Tibetan Plateau Research (ITP) in Beijing. He is the first Asian scientist to win the prestigious Vega Medal in 2017 in the fields of anthropology and geography for his contribution to research on glaciers and the environment on the Tibetan Plateau. Yao received his B.S. in 1978 and M.S in 1982 both from the Department of Geography, Lanzhou University in Gansu, China. He received his Ph.D from the Institute of Geographic Sciences and Natural Resources Research (IGSNRR), Chinese Academy of Sciences (CAS) in 1986. He worked as post-doctor in France and the USA from 1987 to 1990 | Natural_sciences | https://en.wikipedia.org/wiki?curid=36236193 | Yao Tandong |
Yao Tandong He worked at Cold and Arid Regions Environmental and Engineering Research Institute (CAREERI), CAS, which was formerly known as Lanzhou Institute of Glaciology and Geocryology, from 1990 to 2003 and was deputy director of the institute from 1995 to 2000 and director from 2000 to 2003. He has been director of the Institute of Tibetan Plateau Research (ITP), CAS since its founding in 2003. Yao received awards for his research including the Natural Science Award and the Ho Leung Ho Lee Prize. He was recognized by the Science Association of China with a "Distinguished Scientist of China" award in 2005. Yao was elected to the Chinese Academy of Sciences in 2007. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36236193 | Yao Tandong |
John Grattan (1800, Dublin -1871) was an Irish naturalist and anthropologist. was an apothecary in Belfast. He had wide interests in natural history and was a member of the Belfast Natural History Society but is best known for his work on ancient Irish skulls collected by his friend Edmund Getty. He devised a system of skull measurements using an ingenious craniometer. "Grattan's work was almost contemporaneous with that of Anders Retzius, and nearly all of it was done before the German and French Schools had elaborated their schemes of skull measurements" | Natural_sciences | https://en.wikipedia.org/wiki?curid=36243239 | John Grattan |
William Bean (geologist) William Bean (1787–1866) was an English geologist and conchologist. He was a pioneer of Yorkshire geology. In 1859 he sold his collection of over 15,000 fossils (mostly from localities around Scarborough). The majority of his collection was purchased by the British Museum and the Yorkshire Philosophical Society. Bean described several new species of Mollusca, including the whelk "Beringius turtoni", named in honor of William Turton. Bean was associated with the "Magazine of Natural History", and was a friend of Joshua Alder and Albany Hancock. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36246497 | William Bean (geologist) |
Robert Damon (1814 – 4 May 1889) was an English conchologist and geologist. Damon was at first a hosier and glover but with his son Robert Ferris Damon (1845–1929) he established a dealership in natural history specimens in Weymouth. The company supplied museums throughout North and South America, Australia and Europe with much Dorset geological material from the late 1840s to 1914. In 1860 Damon wrote "Geology of Weymouth and the Isles of Portland; with Notes on the Natural History of the Coast and Neighbourhood" which includes a map of the district, geological sections, plates of fossils, and coast views, in 1884 a second edition with archaeological notes was published | Natural_sciences | https://en.wikipedia.org/wiki?curid=36247158 | Robert Damon |
Robert Damon He also wrote (and published himself in 1857) "A catalogue of the shells of Great Britain and Ireland with their synonyms and authorities". Damon died aged 75 at his museum in Weymouth from heart disease. The species "Amoria damonii" Gray, and "Paramelania damoni" were named in his honor. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36247158 | Robert Damon |
Anton Moro Anton Lazzaro Moro (1687 in San Vito al Tagliamento – 1764) was an Italian abbot, geologist and naturalist. He was one of the leading advocates of plutonism in the early debate that confronted plutonism to neptunism, making him described by some authors as an ultraplutonist. He was the first to discriminate sedimentary rocks from volcanic ones by studying the rocks of volcanic islands. In his study of the crustaceans, he discovered fossils petrified in mountains that led him to deduce those rocks were once buried in the sea. | Natural_sciences | https://en.wikipedia.org/wiki?curid=36291124 | Anton Moro |
Theory of the Earth was a publication by James Hutton which laid the foundations for geology. In it he showed that the Earth is the product of natural forces. What could be seen happening today, over long periods of time, could produce what we see in the rocks. It also hypothesized that the age of the Earth was much older than what biblical literalists claim. This idea, uniformitarianism, was used by Charles Lyell in his work, and Lyell's textbook was an important influence on Charles Darwin. The work was first published in 1788 by the Royal Society of Edinburgh, and later in 1795 as two book volumes. Hutton recognized that rocks record the evidence of the past action of processes which still operate today | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294056 | Theory of the Earth |
Theory of the Earth He also anticipated natural selection, as follows: "Those which depart most from the best adapted constitution, will be the most liable to perish, while, on the other hand, those organised bodies, which most approach to the best constitution for the present circumstances, will be best adapted to continue, in preserving themselves and multiplying the individuals of their race". Hutton's prose hindered his theories. They were not taken seriously until 1802, when Edinburgh University mathematics professor John Playfair restated Hutton's geological ideas in clearer English. However, he left out Hutton's thoughts on evolution | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294056 | Theory of the Earth |
Theory of the Earth Charles Lyell in the 1830s popularised the idea of an infinitely repeating cycle (of the erosion of rocks and the building up of sediment). Lyell believed in gradual change, and thought even Hutton gave too much credit to catastrophic changes. Hutton's work was published in different forms and stages: | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294056 | Theory of the Earth |
ViroMed Co., Ltd. (VM BioPharma in the US) is a biotechnology company located in Seoul, Korea with US presence in Atlanta and the San Francisco Bay Area. The company works on DNA and protein-based therapeutics for various life-threatening diseases, along with herbal-based medicines, and nutraceuticals. has five main products in its pipeline targeting cardiovascular disease, cancer, and immune-related disorder, with clinical trials in the US, Korea, and China. The company has established partnerships with global firms including Johnson & Johnson (Biologics Delivery Systems Group of Cordis Corp., USA), SBI Biotech (Japan), and Green Cross (Korea). The company also conducts preclinical developmental studies in the aspects of toxicology, efficacy and pharmacokinetics | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294209 | ViroMed |
ViroMed Phase I and II clinical studies are also carried out. Co., Ltd. (ViroMed) was established in 1996 as ViroMedica Pacific, Inc., later changed to in 1999. The company is headquartered in Seoul, Korea with US presence in Atlanta, GA. has been listed on KOSDAQ (084990) since 2006. As of Jan. 6th, 2017, the total number of issued shares is 15,956,260 with market capitalization approximately at US$1.6 billion. VM202 is a DNA-based medicine designed to express two isoforms of hepatocyte growth factor (HGF), a protein known to induce the formation of new blood vessels and the growth of damaged nerve cells. Currently, VM202 is being tested for 4 major cardiovascular or neurological diseases | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294209 | ViroMed |
ViroMed In all cases, VM202 is delivered by simple intramuscular injection around the affected site. A phase III study for painful diabetic peripheral neuropathy (VM202-DPN) has been successfully initiated in the US in 2016. As of May 2017, over 160 have been randomized in the US among whom over 140 patients have completed their first injections at 21 clinical sites. A phase III study for chronic, non-healing foot ulcer associated with diabetes (VM202-PAD) has received approval from the US FDA and will have patient enrollment in 2017 in the US. After successful phase I trial for coronary artery disease (VM202-CAD), a phase II study is planned as IRB review in clinical sites is currently underway in Korea | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294209 | ViroMed |
ViroMed VM202 has also successfully completed a phase I/II for amyotrophic lateral sclerosis (VM202-ALS), also known as Lou Gehrig's disease, which received orphan drug status and fast track designation from the US FDA. Its phase II IND has been approved by the US FDA in 2016. In 2004, transferred VM202 and associated technologies to Beijing Northland Biotech for commercialization purposes; in 2018, VM202 continued on to phase III clinical trials in China. VM206 is a therapeutic cancer vaccine targeting HER2/neu positive breast or ovarian cancer. Her2/neu is over-expressed in about 30% of breast cancers and is strongly associated with poor prognosis | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294209 | ViroMed |
ViroMed VM206 can elicit an immune response to HER2/neu, which is hoped to reduce the growth and recurrence rate of breast or ovarian cancer. VM501 is a re-engineered form of interleukin 11 (IL-11) targeting chemotherapy-induced thrombocytopenia (CIT) that is said to be less toxic than the existing FDA-approved drugs. According to its website, the company is involved in the following clinical trials: | Natural_sciences | https://en.wikipedia.org/wiki?curid=36294209 | ViroMed |
Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor (multipotent – iMSC, also called an induced multipotent progenitor cell – iMPC) or unipotent – (iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells. Three techniques are widely recognized: In 1895 Thomas Morgan removed one of a frog's two blastomeres and found that amphibians are able to form whole embryos from the remaining part | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This meant that the cells can change their differentiation pathway. In 1924 Spemann and Mangold demonstrated the key importance of cell–cell inductions during animal development. The reversible transformation of cells of one differentiated cell type to another is called metaplasia. This transition can be a part of the normal maturation process, or caused by an inducement. One example is the transformation of iris cells to lens cells in the process of maturation and transformation of retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells In Drosophila imaginal discs, cells have to choose from a limited number of standard discrete differentiation states. The fact that transdetermination (change of the path of differentiation) often occurs for a group of cells rather than single cells shows that it is induced rather than part of maturation. The researchers were able to identify the minimal conditions and factors that would be sufficient for starting the cascade of molecular and cellular processes to instruct pluripotent cells to organize the embryo | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells They showed that opposing gradients of bone morphogenetic protein (BMP) and Nodal, two transforming growth factor family members that act as morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, "in vivo" or "in vitro", uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo. Some types of mature, specialized adult cells can naturally revert to stem cells. For example, "chief" cells express the stem cell marker Troy. While they normally produce digestive fluids for the stomach, they can revert into stem cells to make temporary repairs to stomach injuries, such as a cut or damage from infection | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Moreover, they can make this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, in essence serving as quiescent "reserve" stem cells. Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo. After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves and then differentiate into the cell types needing replacement in the damaged tissue Macrophages can self-renew by local proliferation of mature differentiated cells. In newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget the type of cell they had been | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This capacity to regenerate does not decline with age and may be linked to their ability to make new stem cells from muscle cells on demand. A variety of nontumorigenic stem cells display the ability to generate multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant adult human stem cells that can self-renew. They form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency and can differentiate into endodermal, ectodermal and mesodermal cells both in vitro and in vivo. Other well-documented examples of transdifferentiation and their significance in development and regeneration were described in detail | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Induced totipotent cells can be obtained by reprogramming somatic cells with somatic-cell nuclear transfer (SCNT). The process involves sucking out the nucleus of a somatic (body) cell and injecting it into an oocyte that has had its nucleus removed Using an approach based on the protocol outlined by Tachibana et al., hESCs can be generated by SCNT using dermal fibroblasts nuclei from both a middle-aged 35-year-old male and an elderly, 75-year-old male, suggesting that age-associated changes are not necessarily an impediment to SCNT-based nuclear reprogramming of human cells. Such reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Unfortunately, the cells generated by this technology, potentially are not completely protected from the immune system of the patient (donor of nuclei), because they have the same mitochondrial DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for autologous stem cell transplantation therapy, as for the present, it is not clear whether it can induce an immune response of the patient upon treatment. Induced androgenetic haploid embryonic stem cells can be used instead of sperm for cloning. These cells, synchronized in M phase and injected into the oocyte can produce viable offspring | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells, offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a SCNT method that includes a histone deacetylase inhibitor, trichostatin, added to the cell culture medium, show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors However, research into technologies to develop sperm and egg cells from stem cells raises bioethical issues. Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells For example, the technology could prevent inherited mitochondrial disease from passing to future generations. Mitochondrial genetic material is passed from mother to child. Mutations can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and other neurological diseases. The nucleus from one human egg has been transferred to another, including its mitochondria, creating a cell that could be regarded as having two mothers. The eggs were then fertilised and the resulting embryonic stem cells carried the swapped mitochondrial DNA | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells As evidence that the technique is safe author of this method points to the existence of the healthy monkeys that are now more than four years old – and are the product of mitochondrial transplants across different genetic backgrounds. In late-generation telomerase-deficient (Terc−/−) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming. Other cloning and totipotent transformation achievements have been described. Recently some researchers succeeded to get the totipotent cells without the aid of SCNT. Totipotent cells were obtained using the epigenetic factors such as oocyte germinal isoform of histone | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Reprogramming in vivo, by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice, confers totipotency features. Intraperitoneal injection of such in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic (trophectodermal) markers. The developmental potential of mouse pluripotent stem cells to yield both embryonic and extra-embryonic lineages also can be expanded by microRNA miR-34a deficiency leading to strong induction of endogenous retroviruses MuERV-L (MERVL). iPSc were first obtained in the form of transplantable teratocarcinoma induced by grafts taken from mouse embryos. Teratocarcinoma formed from somatic cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Genetically mosaic mice were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency. It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cell in an undifferentiated state, by supplying the culture medium with various factors. In the 1980s, it became clear that transplanting pluripotent/embryonic stem cells into the body of adult mammals, usually leads to the formation of teratomas, which can then turn into a malignant tumor teratocarcinoma. However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the inner cell mass and often produced a normal chimeric (i.e. composed of cells from different organisms) animal | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche"). In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes. Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells IPSC properties are very similar to ESCs. iPSCs have been shown to support the development of all-iPSC mice using a tetraploid (4n) embryo, the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster. A team headed by Hans Schöler (who discovered the Oct4 gene back in 1989) showed that Oct4 overexpression drives massive off-target gene activation during reprogramming deteriorating the quality of iPSCs | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Comparing to OSKM (Oct4, Sox2, Klf4 and c-Myc)that show abnormal imprinting and differentiation patterns, SKM (Sox2, Klf4 and c-Myc) reprogramming generates iPSCs with high developmental potential (nearly 20-fold higher than that of OSKM) equivalent to embryonic stem cell, as determined by their ability to generate all-iPSC mice through tetraploid embryo complementation An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients. Reprogramming somatic cells to iPSC leads to rejuvenation | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives. Thus, reprogramming leads to the restoration of embryonic telomere length, and hence increases the potential number of cell divisions otherwise limited by the Hayflick limit. However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an immune response, which can be used for medical purposes, or the formation of tumors such as teratoma. The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic protein isoforms | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells So, the immune system might detect and attack cells that are not cooperating properly. A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis (via cytochrome c release across the mitochondrial outer membrane) in human pluripotent stem cells, but not in differentiated cells. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypothesized to be due to the changes undergone by pluripotent stem cell mitochondria in the process of cell differentiation | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This ability of MitoBloCK-6 to separate the pluripotent and differentiated cell lines has the potential to reduce the risk of teratomas and other problems in regenerative medicine. In 2012 other small molecules (selective cytotoxic inhibitors of human pluripotent stem cells – hPSCs) were identified that prevented human pluripotent stem cells from forming teratomas in mice. The most potent and selective compound of them (PluriSIn #1) inhibits stearoyl-coA desaturase (the key enzyme in oleic acid biosynthesis), which finally results in apoptosis. With the help of this molecule the undifferentiated cells can be selectively removed from culture | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells An efficient strategy to selectively eliminate pluripotent cells with teratoma potential is targeting pluripotent stem cell-specific antiapoptotic factor(s) (i.e., survivin or Bcl10). A single treatment with chemical survivin inhibitors (e.g., quercetin or YM155) can induce selective and complete cell death of undifferentiated hPSCs and is claimed to be sufficient to prevent teratoma formation after transplantation. However, it is unlikely that any kind of preliminary clearance, is able to secure the replanting iPSC or ESC. After the selective removal of pluripotent cells, they re-emerge quickly by reverting differentiated cells into stem cells, which leads to tumors | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This may be due to the disorder of let-7 regulation of its target Nr6a1 (also known as Germ cell nuclear factor - GCNF), an embryonic transcriptional repressor of pluripotency genes that regulates gene expression in adult fibroblasts following micro-RNA miRNA loss. Teratoma formation by pluripotent stem cells may be caused by low activity of PTEN enzyme, reported to promote the survival of a small population (0.1–5% of total population) of highly tumorigenic, aggressive, teratoma-initiating embryonic-like carcinoma cells during differentiation. The survival of these teratoma-initiating cells is associated with failed repression of Nanog as well as a propensity for increased glucose and cholesterol metabolism | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells. In connection with the above safety problems, the use iPSC for cell therapy is still limited. However, they can be used for a variety of other purposes - including the modeling of disease, screening (selective selection) of drugs, toxicity testing of various drugs | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The tissue grown from iPSCs, placed in the "chimeric" embryos in the early stages of mouse development, practically do not cause an immune response (after the embryos have grown into adult mice) and are suitable for autologous transplantation At the same time, full reprogramming of adult cells in vivo within tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs. Furthermore, partial reprogramming of cells toward pluripotency in vivo in mice demonstrates that incomplete reprogramming entails epigenetic changes (failed repression of Polycomb targets and altered DNA methylation) in cells that drive cancer development | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells By using solely small molecules, Deng Hongkui and colleagues demonstrated that endogenous "master genes" are enough for cell fate reprogramming. They induced a pluripotent state in adult cells from mice using seven small-molecule compounds. The effectiveness of the method is quite high: it was able to convert 0.02% of the adult tissue cells into iPSCs, which is comparable to the gene insertion conversion rate. The authors note that the mice generated from CiPSCs were "100% viable and apparently healthy for up to 6 months". So, this chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells In 2015 a robust chemical reprogramming system was established with a yield up to 1,000-fold greater than that of the previously reported protocol. So, chemical reprogramming became a promising approach to manipulate cell fates. The fact that human iPSCs capable of forming teratomas not only in humans but also in some animal body, in particular in mice or pigs, allowed to develop a method for differentiation of iPSCs in vivo. For this purpose, iPSCs with an agent for inducing differentiation into target cells are injected to genetically modified pig or mouse that has suppressed immune system activation on human cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The formed teratoma is cut out and used for the isolation of the necessary differentiated human cells by means of monoclonal antibody to tissue-specific markers on the surface of these cells. This method has been successfully used for the production of functional myeloid, erythroid and lymphoid human cells suitable for transplantation (yet only to mice). Mice engrafted with human iPSC teratoma-derived hematopoietic cells produced human B and T cells capable of functional immune responses. These results offer hope that in vivo generation of patient customized cells is feasible, providing materials that could be useful for transplantation, human antibody generation and drug screening applications | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Using MitoBloCK-6 and/or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place even in the teratoma niche, offers hope that the resulting cells are sufficiently stable to stimuli able to cause their transition back to the dedifferentiated (pluripotent) state and therefore safe. A similar in vivo differentiation system, yielding engraftable hematopoietic stem cells from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis, was described by Suzuki et al | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells They noted that neither leukemia nor tumors were observed in recipients after intravenous injection of iPSC-derived hematopoietic stem cells into irradiated recipients. Moreover, this injection resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Such system provides a useful tool for practical application of iPSCs in the treatment of hematologic and immunologic diseases. For further development of this method animal in which is grown the human cell graft, for example mouse, must have so modified genome that all its cells express and have on its surface human SIRPα | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells To prevent rejection after transplantation to the patient of the allogenic organ or tissue, grown from the pluripotent stem cells in vivo in the animal, these cells should express two molecules: CTLA4-Ig, which disrupts T cell costimulatory pathways and PD-L1, which activates T cell inhibitory pathway. See also: . In the near-future, clinical trials designed to demonstrate the safety of the use of iPSCs for cell therapy of the people with age-related macular degeneration, a disease causing blindness through retina damaging, will begin. There are several articles describing methods for producing retinal cells from iPSCs and how to use them for cell therapy | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation. However, clinical trials have been successful: ten patients suffering from retinitis pigmentosa have had their eyesight restored – including a woman who had only 17 percent of her vision left. Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. So there is an urgent need for effective cell therapy and lung tissue engineering | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Several protocols have been developed for generation of the most cell types of the respiratory system, which may be useful for deriving patient-specific therapeutic cells. Some lines of iPSCs have the potentiality to differentiate into male germ cells and oocyte-like cells in an appropriate niche (by culturing in retinoic acid and porcine follicular fluid differentiation medium or seminiferous tubule transplantation). Moreover, iPSC transplantation make a contribution to repairing the testis of infertile mice, demonstrating the potentiality of gamete derivation from iPSCs in vivo and in vitro. The risk of cancer and tumors creates the need to develop methods for safer cell lines suitable for clinical use | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells An alternative approach is so-called "direct reprogramming" – transdifferentiation of cells without passing through the pluripotent state. The basis for this approach was that 5-azacytidine – a DNA demethylation reagent – can cause the formation of myogenic, chondrogenic and adipogeni clones in the immortal cell line of mouse embryonic fibroblasts and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming. Compared with iPSC whose reprogramming requires at least two weeks, the formation of induced progenitor cells sometimes occurs within a few days and the efficiency of reprogramming is usually many times higher. This reprogramming does not always require cell division | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas. For example, Chandrakanthan et al., & Pimanda describe the generation of tissue-regenerative multipotent stem cells (iMS cells) by treating mature bone and fat cells transiently with a growth factor (platelet-derived growth factor–AB (PDGF-AB)) and 5-Azacytidine. These authors claim that: "Unlike primary mesenchymal stem cells, which are used with little objective evidence in clinical practice to promote tissue repair, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner without forming tumors" and so "has significant scope for application in tissue regeneration | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells " Originally only early embryonic cells could be coaxed into changing their identity. Mature cells are resistant to changing their identity once they've committed to a specific kind. However, brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult roundworm "Caenorhabditis elegans" with no requirement for a dedifferentiated intermediate. The cell fate can be effectively manipulated by epigenome editing. In particular, by directly activating of specific endogenous gene expression with CRISPR-mediated activator | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells When dCas9 (that has been modified so that it no longer cuts DNA, but still can be guided to specific sequences and to bind to them) is combined with transcription activators, it can precisely manipulate endogenous gene expression. Using this method, Wei et al., enhanced the expression of endogenous Cdx2 and Gata6 genes by CRISPR-mediated activators, thus directly converted mouse embryonic stem cells into two extraembryonic lineages, i.e., typical trophoblast stem cells and extraembryonic endoderm cells. An analogous approach was used to induce activation of the endogenous Brn2, Ascl1, and Myt1l genes to convert mouse embryonic fibroblasts to induced neuronal cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Thus, transcriptional activation and epigenetic remodeling of endogenous master transcription factors are sufficient for conversion between cell types. The rapid and sustained activation of endogenous genes in their native chromatin context by this approach may facilitate reprogramming with transient methods that avoid genomic integration and provides a new strategy for overcoming epigenetic barriers to cell fate specification. Another way of reprogramming is the simulation of the processes that occur during amphibian limb regeneration. In urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates into limb tissue | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells However, sequential small molecule treatment of the muscle fiber with myoseverin, reversine (the aurora B kinase inhibitor) and some other chemicals: BIO (glycogen synthase-3 kinase inhibitor), lysophosphatidic acid (pleiotropic activator of G-protein-coupled receptors), SB203580 (p38 MAP kinase inhibitor), or SQ22536 (adenylyl cyclase inhibitor) causes the formation of new muscle cell types as well as other cell types such as precursors to fat, bone and nervous system cells. The researchers discovered that GCSF-mimicking antibody can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells that normally develop into white blood cells to become neural progenitor cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The technique enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect. The human gastrointestinal tract is colonized by a vast community of symbionts and commensals. The researchers demonstrate the phenomenon of somatic cell reprograming by bacteria and generation of multipotential cells from adult human dermal fibroblast cells by incorporating Lactic acid bacteria This cellular transdifferentiation is caused by ribosomes and "can occur via donor bacteria that are swallowed and digested by host cells, which may induce ribosomal stress and stimulate cellular developmental plasticity | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells " Schlegel and Liu demonstrated that the combination of feeder cells and a Rho kinase inhibitor (Y-27632) induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal of Y-27632 and feeders allows the cells to differentiate normally | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells CRC technology can generate 2 cells in 5 to 6 days from needle biopsies and can generate cultures from cryopreserved tissue and from fewer than four viable cells. CRCs retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors. The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking. Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Engleman's group describes a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance using CRC system. In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host. While initial studies revealed that co-culturing epithelial cells with Swiss 3T3 cells J2 was essential for CRC induction, with transwell culture plates, physical contact between feeders and epithelial cells is not required for inducing CRCs and more importantly that irradiation of the feeder cells is required for this induction | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Consistent with the transwell experiments, conditioned medium induces and maintains CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells. Riegel et al. demonstrate that mouse ME cells isolated from normal mammary glands or from mouse mammary tumor virus (MMTV)-Neu–induced mammary tumors, can be cultured indefinitely as conditionally reprogrammed cells (CRCs). Cell surface progenitor-associated markers are rapidly induced in normal mouse ME-CRCs relative to ME cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells However, the expression of certain mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops significantly in later passages. Nevertheless, mouse ME-CRCs grown in a three-dimensional extracellular matrix gave rise to mammary acinar structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary tumors express high levels of HER2/neu, as well as tumor-initiating cell markers, such as CD44+, CD49f+ and ESA+ (EpCam). These patterns of expression are sustained in later CRC passages. Early and late passage ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads of syngeneic or nude mice developed vascular tumors that metastasized within 6 weeks of transplantation | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Importantly, the histopathology of these tumors was indistinguishable from that of the parental tumors that develop in the MMTV-Neu mice. Application of the CRC system to mouse mammary epithelial cells provides an attractive model system to study the genetics and phenotype of normal and transformed mouse epithelium in a defined culture environment and in vivo transplant studies. A different approach to CRC is to inhibit CD47 – a membrane protein that is the thrombospondin-1 receptor. Loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells in vitro and in vivo. Thrombospondin-1 is a key environmental signal that inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors. In vivo blockade of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation due to increased proliferative capacity of bone marrow-derived cells and radioprotection of radiosensitive gastrointestinal tissues. Differentiated macrophages can self-renew in tissues and expand long-term in culture | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Under certain conditions macrophages can divide without losing features they have acquired while specializing into immune cells – which is usually not possible with differentiated cells. The macrophages achieve this by activating a gene network similar to one found in embryonic stem cells. Single-cell analysis revealed that, "in vivo", proliferating macrophages can derepress a macrophage-specific enhancer repertoire associated with a gene network controlling self-renewal. This happened when concentrations of two transcription factors named MafB and c-Maf were naturally low or were inhibited for a short time. Genetic manipulations that turned off MafB and c-Maf in the macrophages caused the cells to start a self-renewal program | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The similar network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. Hence macrophages isolated from MafB- and c-Maf-double deficient mice divide indefinitely; the self-renewal depends on c-Myc and Klf4. Indirect lineage conversion is a reprogramming methodology in which somatic cells transition through a plastic intermediate state of partially reprogrammed cells (pre-iPSC), induced by brief exposure to reprogramming factors, followed by differentiation in a specially developed chemical environment (artificial niche) | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This method could be both more efficient and safer, since it does not seem to produce tumors or other undesirable genetic changes and results in much greater yield than other methods. However, the safety of these cells remains questionable. Since lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, a fraction of the cells could acquire pluripotent properties if they do not stop the de-differentation process in vitro or due to further de-differentiation in vivo. A common feature of pluripotent stem cells is the specific nature of protein glycosylation of their outer membrane. That distinguishes them from most nonpluripotent cells, although not white blood cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA-3, SSEA-4, Tra 1-60 and Tra 1-81. Suila Heli et al. speculate that in human stem cells extracellular O-GlcNAc and extracellular O-LacNAc, play a crucial role in the fine tuning of Notch signaling pathway - a highly conserved cell signaling system, that regulates cell fate specification, differentiation, left–right asymmetry, apoptosis, somitogenesis, angiogenesis and plays a key role in stem cell proliferation (reviewed by Perdigoto and Bardin and Jafar-Nejad et al | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells ) Changes in outer membrane protein glycosylation are markers of cell states connected in some way with pluripotency and differentiation. The glycosylation change is apparently not just the result of the initialization of gene expression, but perform as an important gene regulator involved in the acquisition and maintenance of the undifferentiated state. For example, activation of glycoprotein ACA, linking glycosylphosphatidylinositol on the surface of the progenitor cells in human peripheral blood, induces increased expression of genes Wnt, Notch-1, BMI1 and HOXB4 through a signaling cascade PI3K/Akt/mTor/PTEN and promotes the formation of a self-renewing population of hematopoietic stem cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Furthermore, dedifferentiation of progenitor cells induced by ACA-dependent signaling pathway leads to ACA-induced pluripotent stem cells, capable of differentiating in vitro into cells of all three germ layers. The study of lectins' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin Erythrina crista-galli (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells. Cell adhesion protein E-cadherin is indispensable for a robust pluripotent phenotype. During reprogramming for iPS cell generation, N-cadherin can replace function of E-cadherin | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells These functions of cadherins are not directly related to adhesion because sphere morphology helps maintaining the "stemness" of stem cells. Moreover, sphere formation, due to forced growth of cells on a low attachment surface, sometimes induces reprogramming. For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors. Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells' epigenetic state | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Specifically, "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5) – a subunit of H3 methyltranferase – by microgrooved surfaces lead to increased histone H3 acetylation and methylation". Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state. Substrate rigidity is an important biophysical cue influencing neural induction and subtype specification. For example, soft substrates promote neuroepithelial conversion while inhibiting neural crest differentiation of hESCs in a BMP4-dependent manner | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility. Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine leukemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, accompanied by an increase in cell–substratum adhesion and cell spreading. Restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biosubstrates, or by manipulating the cytoskeleton allowed the cells to remain in an undifferentiated and pluripotent state | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA does not promote differentiation. Possible mechanisms of stem cell fate predetermination by physical interactions with the extracellular matrix have been described. A new method has been developed that turns cells into stem cells faster and more efficiently by 'squeezing' them using 3D microenvironment stiffness and density of the surrounding gel. The technique can be applied to a large number of cells to produce stem cells for medical purposes on an industrial scale | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Cells involved in the reprogramming process change morphologically as the process proceeds. This results in physical difference in adhesive forces among cells. Substantial differences in 'adhesive signature' between pluripotent stem cells, partially reprogrammed cells, differentiated progeny and somatic cells allowed to develop separation process for isolation of pluripotent stem cells in microfluidic devices, which is: Stem cells possess mechanical memory (they remember past physical signals) – with the Hippo signaling pathway factors: Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) acting as an intracellular mechanical rheostat—that stores information from past physical environments and influences the cells' fate | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Stroke and many neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis need cell replacement therapy. The successful use of converted neural cells (cNs) in transplantations open a new avenue to treat such diseases. Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed and exhibit very limited proliferative ability that may not provide enough autologous donor cells for transplantation. Self-renewing induced neural stem cells (iNSCs) provide additional advantages over iNs for both basic research and clinical applications | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form iNSCs that self-renew in culture and after transplantation can survive and integrate without forming tumors in mouse brains. INSCs can be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method for autologous transplantation or for the development of cell-based disease models | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Neural chemically induced progenitor cells (ciNPCs) can be generated from mouse tail-tip fibroblasts and human urinary somatic cells without introducing exogenous factors, but - by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, RepSox, an inhibitor of TGF beta signaling pathways), under a physiological hypoxic condition. Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase and TGF-β pathways (where: sodium butyrate (NaB) or Trichostatin A (TSA) could replace VPA, Lithium chloride (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with SB-431542 or Tranilast) show similar efficacies for ciNPC induction. Zhang, et al | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells , also report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components. Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described. Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human astrocytes directly in the brain that are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl1, Brn2a and Myt1l) are activated after transplantation using a drug | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Astrocytes – the most common neuroglial brain cells, which contribute to scar formation in response to injury – can be directly reprogrammed in vivo to become functional neurons that formed networks in mice without the need of cell transplantation. The researchers followed the mice for nearly a year to look for signs of tumor formation and reported finding none. The same researchers have turned scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons in the injured adult spinal cord. Without myelin to insulate neurons, nerve signals quickly lose power | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that cannot propagate to nerve endings and as a consequence lead to cognitive, motor and sensory problems. Transplantation of oligodendrocyte precursor cells (OPCs), which can successfully create myelin sheaths around nerve cells, is a promising potential therapeutic response. Direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells provides a potential source of OPCs. Conversion by forced expression of both eight or of the three transcription factors Sox10, Olig2 and Zfp536, may provide such cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Cell-based in vivo therapies may provide a transformative approach to augment vascular and muscle growth and to prevent non-contractile scar formation by delivering transcription factors or microRNAs to the heart. Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of cardiac core transcription factors ( GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1, Myocardin and ZFPM2) after coronary ligation. These results implicated therapies that can directly remuscularize the heart without cell transplantation | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells However, the efficiency of such reprogramming turned out to be very low and the phenotype of received cardiomyocyte-like cells does not resemble those of a mature normal cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes. Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred. Efficient cardiac differentiation of human iPS cells gave rise to progenitors that were retained within infarcted rat hearts and reduced remodeling of the heart after ischemic damage | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells The team of scientists, who were led by Sheng Ding, used a cocktail of nine chemicals (9C) for transdifferentiation of human skin cells into beating heart cells. With this method, more than 97% of the cells began beating, a characteristic of fully developed, healthy heart cells. The chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs and developed into healthy-looking heart muscle cells within the organ | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells This chemical reprogramming approach, after further optimization, may offer an easy way to provide the cues that induce heart muscle to regenerate locally. In another study, ischemic cardiomyopathy in the murine infarction model was targeted by iPS cell transplantation. It synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from decompensation by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling. One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical Wnt signaling pathway at defined time points in during differentiation, using readily accessible small molecule compounds | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Discovery of the mechanisms controlling the formation of cardiomyocytes led to the development of the drug ITD-1, which effectively clears the cell surface from TGF-β receptor type II and selectively inhibits intracellular TGF-β signaling. It thus selectively enhances the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells. One project seeded decellularized mouse hearts with human iPSC-derived multipotential cardiovascular progenitor cells. The introduced cells migrated, proliferated and differentiated in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the hearts | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells In addition, the heart's extracellular matrix (the substrate of heart scaffold) signalled the human cells into becoming the specialised cells needed for proper heart function. After 20 days of perfusion with growth factors, the engineered heart tissues started to beat again and were responsive to drugs. Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs) "in situ" represents a promising strategy for cardiac regeneration | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Mice exposed "in vivo", to three cardiac transcription factors GMT (Gata4, Mef2c, Tbx5) and the small-molecules: SB-431542 (the transforming growth factor (TGF)-β inhibitor), and XAV939 (the WNT inhibitor) for 2 weeks after myocardial infarction showed significantly improved reprogramming (reprogramming efficiency increased eight-fold) and cardiac function compared to those exposed to only GMT. See also: review The elderly often suffer from progressive muscle weakness and regenerative failure owing in part to elevated activity of the p38α and p38β mitogen-activated kinase pathway in senescent skeletal muscle stem cells | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Subjecting such stem cells to transient inhibition of p38α and p38β in conjunction with culture on soft hydrogel substrates rapidly expands and rejuvenates them that result in the return of their strength. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Myogenic progenitors for potential use in disease modeling or cell-based therapies targeting skeletal muscle could also be generated directly from induced pluripotent stem cells using free-floating spherical culture (EZ spheres) in a culture medium supplemented with high concentrations (100 ng/ml) of fibroblast growth factor-2 (FGF-2) and epidermal growth factor. Unlike current protocols for deriving hepatocytes from human fibroblasts, Saiyong Zhu et al., (2014) did not generate iPSCs but, using small molecules, cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) were efficiently differentiated | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of human primary adult hepatocytes. iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state. These results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Cocktail of small molecules, Y-27632, A-83-01 (a TGFβ kinase/activin receptor like kinase (ALK5) inhibitor), and CHIR99021 (potent inhibitor of GSK-3), can convert rat and mouse mature hepatocytes in vitro into proliferative bipotent cells – CLiPs (chemically induced liver progenitors). CLiPs can differentiate into both mature hepatocytes and biliary epithelial cells that can form functional ductal structures. In long-term culture CLiPs did not lose their proliferative capacity and their hepatic differentiation ability, and can repopulate chronically injured liver tissue | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells Complications of Diabetes mellitus such as cardiovascular diseases, retinopathy, neuropathy, nephropathy and peripheral circulatory diseases depend on sugar dysregulation due to lack of insulin from pancreatic beta cells and can be lethal if they are not treated. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs). Unfortunately, human PSC-derived insulin-expressing cells resemble human fetal β cells rather than adult β cells. In contrast to adult β cells, fetal β cells seem functionally immature, as indicated by increased basal glucose secretion and lack of glucose stimulation and confirmed by RNA-seq of whose transcripts | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells An alternative strategy is the conversion of fibroblasts towards distinct endodermal progenitor cell populations and, using cocktails of signalling factors, successful differentiation of these endodermal progenitor cells into functional beta-like cells both in vitro and in vivo. Overexpression of the three transcription factors, PDX1 (required for pancreatic bud outgrowth and beta-cell maturation), NGN3 (required for endocrine precursor cell formation) and MAFA (for beta-cell maturation) combination (called PNM) can lead to the transformation of some cell types into a beta cell-like state. An accessible and abundant source of functional insulin-producing cells is intestine | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells possibly acceptable for transplantation. Adult proximal tubule cells were directly transcriptionally reprogrammed to nephron progenitors of the embryonic kidney, using a pool of six genes of instructive transcription factors (SIX1, SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail homolog 2 (SNAI2)) that activated genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule cell line. The generation of such cells may lead to cellular therapies for adult renal disease. Embryonic kidney organoids placed into adult rat kidneys can undergo onward development and vascular development | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells As blood vessels age, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including myocardial infarction, ischemic stroke and atherosclerosis of arteries supplying the heart, brain and lower extremities. So, an important goal is to stimulate vascular growth for the collateral circulation to prevent the exacerbation of these diseases. Induced Vascular Progenitor Cells (iVPCs) are useful for cell-based therapy designed to stimulate coronary collateral growth. They were generated by partially reprogramming endothelial cells. The vascular commitment of iVPCs is related to the epigenetic memory of endothelial cells, which engenders them as cellular components of growing blood vessels | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |
Induced stem cells That is why, when iVPCs were implanted into myocardium, they engrafted in blood vessels and increased coronary collateral flow better than iPSCs, mesenchymal stem cells, or native endothelial cells. Ex vivo genetic modification can be an effective strategy to enhance stem cell function. For example, cellular therapy employing genetic modification with Pim-1 kinase (a downstream effector of Akt, which positively regulates neovasculogenesis) of bone marrow–derived cells or human cardiac progenitor cells, isolated from failing myocardium results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance | Natural_sciences | https://en.wikipedia.org/wiki?curid=36315057 | Induced stem cells |