Human Stem Cells for Tissue Repair (2007)

The primary application for hematopoietic stem cell transplantation has traditionally been to reconstitute blood cell lineages that had formed abnormally because of genetic mutations, or that had been eradicated to treat a disease such as leukemia. However, in recent years, compelling data has suggested that stem cells from the bone marrow might have far greater potential, and might be able to repair damaged or diseased tissues outside of the blood-forming compartment. Much attention has been paid to the concept of "stem cell plasticity," and the hope that stem cells could be used to repair damaged tissues has generated immense excitement in many fields.Several types of adult human stem cells have been identified and studied in tissue repair applications. Most popular are hematopoietic stem cells, which can reconstitute the entire blood system, and also mesenchymal stem cells, which have the potential to form bone, cartilage, muscle, and fat. Our group studies tissue repair by both hematopoietic and mesenchymal stem cells, isolated from bone marrow, cord blood, and adipose tissue, in immune-deficient mouse models of injury and disease.Immune-deficient mouse models of tissue damage provide a system in which human stem cell migration to sites of damage and subsequent contribution to repair can be carefully evaluated. Popular strains have been discussed in a review paper [1Meyerrose T.E. Herrbrich P. Hess D.A. Nolta J.A. IImmune-deficient mouse models for analysis of human stem cells.Biotechniques. 2003; 35: 1262-1272PubMed Google Scholar], and newer strains such as NOD/SCID/IL2RG−/− (deficient in the common gamma chain of IL-2 and other lymphoid cytokines) are available. The beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mouse [2Hofling A.A. Vogler C. Creer M.H. Sands M.S. Engraftment of human CD34+ cells leads to widespread distribution of donor-derived cells and correction of tissue pathology in a novel murine xenotransplantation model of lysosomal storage disease.Blood. 2003; 101: 2054-2063Crossref PubMed Scopus (35) Google Scholar] allows the sensitive detection of individual unmarked donor cells (mouse, human, canine, etc.) in engrafted tissues by normal levels of the enzyme, without reliance on the continued expression of human cell surface markers or in situ hybridization. A simple substrate reaction is used on tissue slides. This mouse is highly useful for tissue repair studies, because the transplanted cells can be found in the tissues, by flow cytometry or on slides, without the use of antibody technology. This reduces background and errors in interpretation. Another benefit is that the transplanted cells do not need to be first manipulated to tag them with a vector, membrane dye, or other particle that would identify them later; they are detected based only on their innate expression of the enzyme beta-glucuronidase, absent in the mice.Immune-deficient mice provide easily accessible in vivo models for studying human stem cell migration, engraftment, and contribution to the repair of tissue damage. They can be used to test tissue repair strategies, because most of the cytokines, chemokines, and inflammatory modulators involved with stem cell recruitment and activation are conserved from mouse to humans. Hematopoietic stem cells from adult sources such as bone marrow (BM), mobilized peripheral blood (MPB), adipose tissue, and umbilical cord blood (UCB) have been shown, in our laboratory and others, to promote tissue repair in immune-deficient mouse models. Different populations of stem cells have been described to contribute to the regeneration of muscle [3Galmiche M.C. Koteliansky V.E. Briere J. Herve P. Charbord P. Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway.Blood. 1993; 82: 66-76Crossref PubMed Google Scholar, 4Williams J.T. Southerland S.S. Souza J. Calcutt A.F. Cartledge R.G. Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes.Am Surg. 1999; 65: 22-26PubMed Google Scholar], liver [5Petersen B.E. Bowen W.C. Patrene K.D. et al.Bone marrow as a potential source of hepatic oval cells.Science. 1999; 284: 1168-1170Crossref PubMed Scopus (2177) Google Scholar, 6Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229-1234Crossref PubMed Scopus (2127) Google Scholar, 7Theise N.D. Badve S. Saxena R. et al.Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation.Hepatology. 2000; 31: 235-240Crossref PubMed Scopus (895) Google Scholar, 8Theise N.D. Nimmakayalu M. Gardner R. et al.Liver from bone marrow in humans.Hepatology. 2000; 32: 11-16Crossref PubMed Scopus (1153) Google Scholar], heart [9Jackson K.A. Majka S.M. Wang H. et al.Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.J Clin Invest. 2001; 107: 1395-1402Crossref PubMed Scopus (1764) Google Scholar, 10Orlic D. Kajstura J. Chimenti S. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701-705Crossref PubMed Scopus (4670) Google Scholar, 11Wu G.D. Nolta J.A. Jin Y.S. et al.Migration of mesenchymal stem cells to heart allografts during chronic rejection.Transplantation. 2003; 75: 679-685Crossref PubMed Scopus (163) Google Scholar, 12Zimmet J.M. Hare J.M. Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy.Basic Res Cardiol. 2005; 100: 471-481Crossref PubMed Scopus (126) Google Scholar], and to regenerate vasculature [13Crisa L. Cirulli V. Smith K.A. Ellisman M.H. Torbett B.E. Salomon D.R. Human cord blood progenitors sustain thymic T-cell development and a novel form of angiogenesis.Blood. 1999; 94: 3928-3940PubMed Google Scholar, 14Peichev M. Naiyer A.J. Pereira D. et al.Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors.Blood. 2000; 95: 952-958Crossref PubMed Google Scholar, 15Davidoff A.M. Ng C.Y. Brown P. et al.Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice.Clin Cancer Res. 2001; 7: 2870-2879PubMed Google Scholar], although the mechanisms by which they accomplish this are still not well understood. Stem cells are known, however, to secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities. One theory of tissue repair and regeneration by adult stem cells is that the mechanism of action is based upon the innate functions of the stem cells: the injected stem cells home to the injured area, in particular to hypoxic and/or inflamed areas, and release trophic factors that hasten endogenous repair. These secreted bioactive factors suppress the local immune system, enhance angiogenesis, inhibit fibrosis and apoptosis, and stimulate recruitment, retention, mitosis, and differentiation of tissue-residing stem cells. These effects, which are referred to as trophic effects, are distinct from the direct differentiation of stem cells into the tissue to be regenerated.Data from our lab and others show that injected adipose and BM-derived MSC lodge in multiple tissues following various routes of administration into sublethally irradiated immune-deficient mice [16Meyerrose T.E. De Ugarte D.A. Hofling A.A. et al.In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models.Stem Cells. 2007; 25: 220-227Crossref PubMed Scopus (154) Google Scholar]. Yet in models of acute local injury, MSC appear to preferentially home to, or accumulate in, the damaged tissue [11Wu G.D. Nolta J.A. Jin Y.S. et al.Migration of mesenchymal stem cells to heart allografts during chronic rejection.Transplantation. 2003; 75: 679-685Crossref PubMed Scopus (163) Google Scholar]. Our group has studied the trafficking of human BM and UCB-derived aldehyde dehydrogenase (ALDH)+, CD34+, and more highly purified subpopulations, and of BM and adipose tissue-derived mesenchymal stem cells to damaged heart, liver, muscle, pancreas, and to the ischemic limbs of immune-deficient mice. Cell trafficking and functional outcomes from intravenous injection of the stem cell populations versus nonstem cell controls (ie, ALDH hi versus ALDH lo sorted populations) were assessed. Trafficking was determined using fluorescent nanoparticle labeling and in vivo dynamic imaging. Endpoints were determined by FACS analysis and by tissue staining using the NOD/SCID/MPSVII mouse, where unmarked donor-derived cells can be easily identified using a simple enzymatic substrate reaction. Within each study, mice were assessed in groups large enough to achieve statistical significance. The groups that had received the stem cell populations demonstrated improved regional blood flow and tissue function, compared with the nonstem cell-injected control groups, at various time points after transplantation. However, very few donor marker-positive cells were found incorporated into vascular structures or in the repaired tissue. Tissue staining in the damaged regions revealed that the transplanted human cells had undergone very few cell divisions after homing to the area of hypoxia or inflammation.The paucity of human cells remaining in the tissue after repair suggest that the tissue improvements that were observed were not the result of generation of transplanted cell-derived endothelial cells, muscle, liver, or beta cells, but suggest that cytokines secreted from transplanted cells potentiated angiogenic activity and tissue repair from endogenous murine cells. Although the combinations of factors involved are still being established, our data indicate that adult human stem cells do not become a significant part of the damaged tissue, but rapidly home to and persist only temporarily at a site of hypoxia or inflammation to exert significant trophic effects on tissue repair.It is important to note that, with over 400 mice now analyzed in these tissue repair experiments, no adult human stem cell-derived tumors have ever been observed. The mouse strains used have no capacity to reject the human cells, and thus were a valid model for testing the tumorigenesis abilities of adult stem cells (Dao, Bauer et al, submitted). Both MSC and HSC have been tested extensively without a single occurrence of a stem cell-derived tumor. However, the immune-compromised mice were susceptible to human leukemias, caused by preexisting leukemic or preleukemic cells in the transplanted cell populations. The spontaneous emergence of the leukemias would likely not have occurred in the presence of functioning NK cells in the mice.In contrast to the hematopoietic and mesenchymal cells that have been isolated using standard techniques, novel populations of cells have been identified by investigators who "think outside the box," as exemplified by exciting work done in the laboratory headed by Mariusz Ratajczak. In addition to cytokines, Ratajczak et al. [17Ratajczak J. Wysoczynski M. Hayek T. Janowska-Wieczorek A. Rataczak H.Z. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (1039) Google Scholar] have shown that microvesicles (MV) can play a role in cell-cell interactions. MV are tiny, between 100 nm to 1 μm, are shed by cells, and can be vehicles for transferring mRNA and can activate various signaling pathways. Ratajczak's group found that microparticles (MP), MV shed from platelets, can be used to heighten the rapidity of HSC engraftment as well as enhance the level of engraftment in lethally irradiated mice [18Janowska-Wieczorek A. Majka M. Kijowski J. et al.Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment.Blood. 2001; 98: 3143-3149Crossref PubMed Scopus (280) Google Scholar]. Furthermore, when MV from human embryonic stem cells were added to HSCs, they increased the pluripotency of the cells as well as upregulating expression of Oct-4, Rex-1, and Nanog, cellular markers of pluripotency [19Ratajczak J. Miekus K. Kucia M. et al.Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.Leukemia. 2006; 20: 847-856Crossref PubMed Scopus (1140) Google Scholar].Mitochondria have also been shown to play a role in cellular repair. It has been shown that MSC, as well as other cell types, are able to transfer their mitochondria to other cells to rescue the cells from death [20Spees J.L. Olson S.D. Whitney M.J. Prockop D.J. Mitochondrial transfer between cells can rescue aerobic respiration.Proc Natl Acad Sci USA. 2006; 103: 1283-1288Crossref PubMed Scopus (660) Google Scholar, 21Redmond Jr., D.E. Bjugstad K.B. et al.Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells.Proc Natl Acad Sci USA. 2007; 104: 12175-12180Crossref PubMed Scopus (283) Google Scholar]. In this study, MSC were added to cells treated with ethidium bromide and were able to restore the cell's aerobic respiration as well as their ability to expand. The restoration of cellular functions was attributed to active mitochondrial transfer. Coculture with mitochondria alone did not result in restored function, nor was there nuclear DNA present, indicating that the effects were not because of cell fusion.Adult stem cells cannot create an entire tissue, as can embryonic cells. However, under the right conditions, adult stem cells can act as the "paramedics of the body," rushing to areas of hypoxia and rapidly causing revascularization and releasing trophic factors to aide in tissue repair, early after tissue injury. In a seminal study by Evan Snyder's group, using a primate human Stem Cells were injected and were found to to the damaged of the The stem cells were found to both endogenous repair in the damaged as well as to differentiate into [20Spees J.L. Olson S.D. Whitney M.J. Prockop D.J. Mitochondrial transfer between cells can rescue aerobic respiration.Proc Natl Acad Sci USA. 2006; 103: 1283-1288Crossref PubMed Scopus (660) Google Scholar]. The active of the is for the active rescue of adult stem and addition to the cell types described human embryonic stem cells are being with the hope that they can repair tissues and more the tissue, as has been for murine embryonic stem cells. these cells were first in the is but transplantation models are and more models of disease and tissue injury in that are immune can the human cell need to be to these The of embryonic and adult stem cell could also for tissue repair, and engraftment and for the injured need to be done to the many of this to the most stem to our many who need The primary application for hematopoietic stem cell transplantation has traditionally been to reconstitute blood cell lineages that had formed abnormally because of genetic mutations, or that had been eradicated to treat a disease such as leukemia. However, in recent years, compelling data has suggested that stem cells from the bone marrow might have far greater potential, and might be able to repair damaged or diseased tissues outside of the blood-forming compartment. Much attention has been paid to the concept of "stem cell plasticity," and the hope that stem cells could be used to repair damaged tissues has generated immense excitement in many types of adult human stem cells have been identified and studied in tissue repair applications. Most popular are hematopoietic stem cells, which can reconstitute the entire blood system, and also mesenchymal stem cells, which have the potential to form bone, cartilage, muscle, and fat. Our group studies tissue repair by both hematopoietic and mesenchymal stem cells, isolated from bone marrow, cord blood, and adipose tissue, in immune-deficient mouse models of injury and mouse models of tissue damage provide a system in which human stem cell migration to sites of damage and subsequent contribution to repair can be carefully evaluated. Popular strains have been discussed in a review paper [1Meyerrose T.E. Herrbrich P. Hess D.A. Nolta J.A. IImmune-deficient mouse models for analysis of human stem cells.Biotechniques. 2003; 35: 1262-1272PubMed Google Scholar], and newer strains such as NOD/SCID/IL2RG−/− (deficient in the common gamma chain of IL-2 and other lymphoid cytokines) are available. The beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mouse [2Hofling A.A. Vogler C. Creer M.H. Sands M.S. Engraftment of human CD34+ cells leads to widespread distribution of donor-derived cells and correction of tissue pathology in a novel murine xenotransplantation model of lysosomal storage disease.Blood. 2003; 101: 2054-2063Crossref PubMed Scopus (35) Google Scholar] allows the sensitive detection of individual unmarked donor cells (mouse, human, canine, etc.) in engrafted tissues by normal levels of the enzyme, without reliance on the continued expression of human cell surface markers or in situ hybridization. A simple substrate reaction is used on tissue slides. This mouse is highly useful for tissue repair studies, because the transplanted cells can be found in the tissues, by flow cytometry or on slides, without the use of antibody technology. This reduces background and errors in interpretation. Another benefit is that the transplanted cells do not need to be first manipulated to tag them with a vector, membrane dye, or other particle that would identify them later; they are detected based only on their innate expression of the enzyme beta-glucuronidase, absent in the mice. mice provide easily accessible in vivo models for studying human stem cell migration, engraftment, and contribution to the repair of tissue damage. They can be used to test tissue repair strategies, because most of the cytokines, chemokines, and inflammatory modulators involved with stem cell recruitment and activation are conserved from mouse to humans. Hematopoietic stem cells from adult sources such as bone marrow (BM), mobilized peripheral blood (MPB), adipose tissue, and umbilical cord blood (UCB) have been shown, in our laboratory and others, to promote tissue repair in immune-deficient mouse models. Different populations of stem cells have been described to contribute to the regeneration of muscle [3Galmiche M.C. Koteliansky V.E. Briere J. Herve P. Charbord P. Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway.Blood. 1993; 82: 66-76Crossref PubMed Google Scholar, 4Williams J.T. Southerland S.S. Souza J. Calcutt A.F. Cartledge R.G. Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes.Am Surg. 1999; 65: 22-26PubMed Google Scholar], liver [5Petersen B.E. Bowen W.C. Patrene K.D. et al.Bone marrow as a potential source of hepatic oval cells.Science. 1999; 284: 1168-1170Crossref PubMed Scopus (2177) Google Scholar, 6Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229-1234Crossref PubMed Scopus (2127) Google Scholar, 7Theise N.D. Badve S. Saxena R. et al.Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation.Hepatology. 2000; 31: 235-240Crossref PubMed Scopus (895) Google Scholar, 8Theise N.D. Nimmakayalu M. Gardner R. et al.Liver from bone marrow in humans.Hepatology. 2000; 32: 11-16Crossref PubMed Scopus (1153) Google Scholar], heart [9Jackson K.A. Majka S.M. Wang H. et al.Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.J Clin Invest. 2001; 107: 1395-1402Crossref PubMed Scopus (1764) Google Scholar, 10Orlic D. Kajstura J. Chimenti S. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701-705Crossref PubMed Scopus (4670) Google Scholar, 11Wu G.D. Nolta J.A. Jin Y.S. et al.Migration of mesenchymal stem cells to heart allografts during chronic rejection.Transplantation. 2003; 75: 679-685Crossref PubMed Scopus (163) Google Scholar, 12Zimmet J.M. Hare J.M. Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy.Basic Res Cardiol. 2005; 100: 471-481Crossref PubMed Scopus (126) Google Scholar], and to regenerate vasculature [13Crisa L. Cirulli V. Smith K.A. Ellisman M.H. Torbett B.E. Salomon D.R. Human cord blood progenitors sustain thymic T-cell development and a novel form of angiogenesis.Blood. 1999; 94: 3928-3940PubMed Google Scholar, 14Peichev M. Naiyer A.J. Pereira D. et al.Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors.Blood. 2000; 95: 952-958Crossref PubMed Google Scholar, 15Davidoff A.M. Ng C.Y. Brown P. et al.Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice.Clin Cancer Res. 2001; 7: 2870-2879PubMed Google Scholar], although the mechanisms by which they accomplish this are still not well understood. Stem cells are known, however, to secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities. One theory of tissue repair and regeneration by adult stem cells is that the mechanism of action is based upon the innate functions of the stem cells: the injected stem cells home to the injured area, in particular to hypoxic and/or inflamed areas, and release trophic factors that hasten endogenous repair. These secreted bioactive factors suppress the local immune system, enhance angiogenesis, inhibit fibrosis and apoptosis, and stimulate recruitment, retention, mitosis, and differentiation of tissue-residing stem cells. These effects, which are referred to as trophic effects, are distinct from the direct differentiation of stem cells into the tissue to be from our lab and others show that injected adipose and BM-derived MSC lodge in multiple tissues following various routes of administration into sublethally irradiated immune-deficient mice [16Meyerrose T.E. De Ugarte D.A. Hofling A.A. et al.In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models.Stem Cells. 2007; 25: 220-227Crossref PubMed Scopus (154) Google Scholar]. Yet in models of acute local injury, MSC appear to preferentially home to, or accumulate in, the damaged tissue [11Wu G.D. Nolta J.A. Jin Y.S. et al.Migration of mesenchymal stem cells to heart allografts during chronic rejection.Transplantation. 2003; 75: 679-685Crossref PubMed Scopus (163) Google Scholar]. Our group has studied the trafficking of human BM and UCB-derived aldehyde dehydrogenase (ALDH)+, CD34+, and more highly purified subpopulations, and of BM and adipose tissue-derived mesenchymal stem cells to damaged heart, liver, muscle, pancreas, and to the ischemic limbs of immune-deficient mice. Cell trafficking and functional outcomes from intravenous injection of the stem cell populations versus nonstem cell controls (ie, ALDH hi versus ALDH lo sorted populations) were assessed. Trafficking was determined using fluorescent nanoparticle labeling and in vivo dynamic imaging. Endpoints were determined by FACS analysis and by tissue staining using the NOD/SCID/MPSVII mouse, where unmarked donor-derived cells can be easily identified using a simple enzymatic substrate reaction. Within each study, mice were assessed in groups large enough to achieve statistical significance. The groups that had received the stem cell populations demonstrated improved regional blood flow and tissue function, compared with the nonstem cell-injected control groups, at various time points after transplantation. However, very few donor marker-positive cells were found incorporated into vascular structures or in the repaired tissue. Tissue staining in the damaged regions revealed that the transplanted human cells had undergone very few cell divisions after homing to the area of hypoxia or The paucity of human cells remaining in the tissue after repair suggest that the tissue improvements that were observed were not the result of generation of transplanted cell-derived endothelial cells, muscle, liver, or beta cells, but suggest that cytokines secreted from transplanted cells potentiated angiogenic activity and tissue repair from endogenous murine cells. Although the combinations of factors involved are still being established, our data indicate that adult human stem cells do not become a significant part of the damaged tissue, but rapidly home to and persist only temporarily at a site of hypoxia or inflammation to exert significant trophic effects on tissue repair. It is important to note that, with over 400 mice now analyzed in these tissue repair experiments, no adult human stem cell-derived tumors have ever been observed. The mouse strains used have no capacity to reject the human cells, and thus were a valid model for testing the tumorigenesis abilities of adult stem cells (Dao, Bauer et al, submitted). Both MSC and HSC have been tested extensively without a single occurrence of a stem cell-derived tumor. However, the immune-compromised mice were susceptible to human leukemias, caused by preexisting leukemic or preleukemic cells in the transplanted cell populations. The spontaneous emergence of the leukemias would likely not have occurred in the presence of functioning NK cells in the mice. In contrast to the hematopoietic and mesenchymal cells that have been isolated using standard techniques, novel populations of cells have been identified by investigators who "think outside the box," as exemplified by exciting work done in the laboratory headed by Mariusz Ratajczak. In addition to cytokines, Ratajczak et al. [17Ratajczak J. Wysoczynski M. Hayek T. Janowska-Wieczorek A. Rataczak H.Z. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication.Leukemia. 2006; 20: 1487-1495Crossref PubMed Scopus (1039) Google Scholar] have shown that microvesicles (MV) can play a role in cell-cell interactions. MV are tiny, between 100 nm to 1 μm, are shed by cells, and can be vehicles for transferring mRNA and can activate various signaling pathways. Ratajczak's group found that microparticles (MP), MV shed from platelets, can be used to heighten the rapidity of HSC engraftment as well as enhance the level of engraftment in lethally irradiated mice [18Janowska-Wieczorek A. Majka M. Kijowski J. et al.Platelet-derived microparticles bind to hematopoietic stem/progenitor cells and enhance their engraftment.Blood. 2001; 98: 3143-3149Crossref PubMed Scopus (280) Google Scholar]. Furthermore, when MV from human embryonic stem cells were added to HSCs, they increased the pluripotency of the cells as well as upregulating expression of Oct-4, Rex-1, and Nanog, cellular markers of pluripotency [19Ratajczak J. Miekus K. Kucia M. et al.Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery.Leukemia. 2006; 20: 847-856Crossref PubMed Scopus (1140) Google Scholar]. have also been shown to play a role in cellular repair. It has been shown that MSC, as well as other cell types, are able to transfer their mitochondria to other cells to rescue the cells from death [20Spees J.L. Olson S.D. Whitney M.J. Prockop D.J. Mitochondrial transfer between cells can rescue aerobic respiration.Proc Natl Acad Sci USA. 2006; 103: 1283-1288Crossref PubMed Scopus (660) Google Scholar, 21Redmond Jr., D.E. Bjugstad K.B. et al.Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells.Proc Natl Acad Sci USA. 2007; 104: 12175-12180Crossref PubMed Scopus (283) Google Scholar]. In this study, MSC were added to cells treated with ethidium bromide and were able to restore the cell's aerobic respiration as well as their ability to expand. The restoration of cellular functions was attributed to active mitochondrial transfer. Coculture with mitochondria alone did not result in restored function, nor was there nuclear DNA present, indicating that the effects were not because of cell stem cells cannot create an entire tissue, as can embryonic cells. However, under the right conditions, adult stem cells can act as the "paramedics of the body," rushing to areas of hypoxia and rapidly causing revascularization and releasing trophic factors to aide in tissue repair, early after tissue injury. In a seminal study by Evan Snyder's group, using a primate human Stem Cells were injected and were found to to the damaged of the The stem cells were found to both endogenous repair in the damaged as well as to differentiate into [20Spees J.L. Olson S.D. Whitney M.J. Prockop D.J. Mitochondrial transfer between cells can rescue aerobic respiration.Proc Natl Acad Sci USA. 2006; 103: 1283-1288Crossref PubMed Scopus (660) Google Scholar]. The active of the is for the active rescue of adult stem and cells. In addition to the cell types described human embryonic stem cells are being with the hope that they can repair tissues and more the tissue, as has been for murine embryonic stem cells. these cells were first in the is but transplantation models are and more models of disease and tissue injury in that are immune can the human cell need to be to these The of embryonic and adult stem cell could also for tissue repair, and engraftment and for the injured need to be done to the many of this to the most stem to our many who need