Stem Cell Based Tissue Engineering and Regenerative Medicine: A Review Focusing on Adult Stem Cells

In the past 30 years, the field of tissue engineering has continued on a fast paced march. Early discoveries in embryonic stem cells fueled a wave of research that led to wild claims about regenerating nonfunctioning organs. Although we are still a far way away from being able to grow functional organs in a Petrei dish, the field continues to progress forward, and new clinical trials begin often that apply the use of stem cell based solutions for regenerative medicine and tissue engineering. Current trends have focused more on adult stem cells for these tissue based therapies and regenerative medicine as they offer an autogenic source, and are less tumorigenic than their embryonic and induced-pluripotent stem cell counter parts. Current therapies in myocardial tissue repair, neural tissue repair, diabetes, osteogenic and chondrogenic differentiation are reviewed. Classes of Stem Cells Embryonic Stem Cells (ESC) Derived from the inner cell mass of in vitro fertilized blastocyst-stage embryos prior to germ layer formation, ESC’s are the cell population that all cells of the mature body are formed from. With appropriate culture conditions, including growth cocktails, co-culture with differentiated cells, and various other protocols, these cells have been shown to be pluripotent or capable of differentiating into cells from all three of the developmental germ layers, endoderm, mesoderm, and ectoderm. Human ESC’s (hESC) were first isolated in 1998 by James Thomson, using in vitro fertilized embryos, and were shown to form teratomas, or tumors with all three germ layers present. [1] Issues associated with teratoma formation, and immunogenicity concerns; however, have limited the clinical application of hESC’s. Associated tumorigenisis with these cells is believed to be correlated to the length of culture of these cells, as it is immortal cells that are inherently selected for. Recent developments, however, have shown that by differentiating ESC’s prior to implantation and sorting for undifferentiated cells, the risk of teratoma formation decreases. [2,3] This has led to the creation of two approved clinical trials that are currently under way. One trial is using ESC derived retinal pigmented epithelia (RPE) for transplantation in patients with Stargardt’s Macular Degeneration, this trial was approved by the Food and Drug Administration in November of 2011, and still actively recruiting patients. [4] Other active clinical trials underway using ESC’s are for spinal cord injury repair. In addition to the risk of tumorigenicity, questions regarding the immunogenicity have also been raised in accordance with the use of ESC’s. Since these stem cells are allogeneic, they will inevitably pose a risk of host rejection post transplantation. Current standard of care practices for patients receiving allogeneic cell transplantation involves the use of immunosuppressive drugs to prevent overall immune Figure 1-­‐Derivation of Embryonic Stem Cells rejection, however this is imperfect solution as it makes the patient more susceptible to infection, and the previously mentioned tumor formation. [5] Induced Pluripotent Stem (iPS) Cells New research has shown that through induction of specific transcription factors and growing cells in conditions replicating the embryonic environment, somatic cells, or fully differentiated cells, can be reprogrammed to an embryonic like state. Such cells are called induced pluripotent stem (iPS) cells. Takahasi and Yamanaka first demonstrated the efficacy of genetic reprogramming of these cells in 2006. Results of this study showed that transfection of c-Myc, Sox2, Klf4, and Oct 3/4 genes are required for the genetic reprogramming of these cells, and removal of one of these genes does not lead to pluripotency in somatic cells. [6] Further studies by Thomson identified Nanog, Oct4, Sox2, and Lin28, as capable of reprogramming somatic cells to a pluripotent state. Significance of these results are that c-Myc had previously been shown to induce differentiation and apoptosis of hESC, in addition to being a known oncogene. [7] Both groups showed that these genetically reprogrammed cells possess the ability to differentiate into cells from all three embryonic germ layers, with some cells being able to accomplish this after 30 passages. These cells also exhibit the embryonic like morphology. It is now known that the only factor necessary for pluripotency is Oct4, and either Sox2 or Nanog. [8]