Adult Stem Cells and Tissue Repair

Adult stem cells and tissue repair

MKo¨ rbling1, Z Estrov2 and R Champlin1

1Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; and 2Department of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Summary: cell transplantation model using the Y chromosome as a marker. However, if stringent criteria are used to judge Recently, adult stem cells originating from bone marrow reports that stem cells deviate from their predetermined or peripheral blood have been suggested to contribute to differentiation pathway to generate cells outside their own repair and genesis of cells specific for liver, cardiac and tissue, only a few reports published so far can stand up to skeletal muscle, gut, and brain tissue. The mechanism critical review.1,2 The findings of those studies fulfill at least involved has been termed transdifferentiation, although in part the following criteria: other explanations including cell fusion have been 1. the source of the stem cells must be clearly identified (eg, postulated. Using adult stem cells to generate or repair Y chromosome, green fluorescence protein, etc); solid organ tissue obviates the immunologic, ethical, and 2. transdifferentiated cells must become an integral part of teratogenic issues that accompany embryonic stem cells. the surrounding tissue; Bone Marrow Transplantation (2003) 32, S23–S24. 3. transdifferentiated cells must function in the same way doi:10.1038/sj.bmt.1703939 as the surrounding organ-specific cells do. Keywords: adult stem cells; developmental stem cell 1 plasticity; stem cell transdifferentiation; regenerative As shown by Krause et al transplantation of a single medicine hematopoietic stem cell with self-renewal capacity resulted in not only complete and permanent reconstitution of hematopoietic tissue but also generation of epithelial cells in the liver, lungs, gastrointestinal tract, and skin. Lagasse et al2 transplanted 50–1000 hematopoietic stem cells into Stem cells are defined as being clonogenic, having self- mice with a fumarylacetoacetate hydrolase deficiency to renewal capacity throughout lifetime and giving rise to show that, besides hematopoietic reconstitution, biochem- terminally differentiated cells of various cell lineages. Their ical liver function was restored. Although the latter differentiation pathway is unidirectional, passing through experimental design provided evidence of the function of the stage of lineage commitment and finally generating transdifferentiated cells, the clonal origin of those cells was terminally differentiated cells. Adult stem cell differentiation not clearly established. However, in a follow-up study, is traditionally believed to be restricted to the tissue in which Wagers et al group recently reported little evidence of any the stem cells reside (eg, hematopoietic stem cells generate developmental plasticity of adult hematopoietic stem cells blood cells, liver progenitor cells (oval cells) produce tested on a clonal level.3 hepatocytes and cholangiocytes). Hematopoietic stem cells The stem cell transdifferentiation model is only one of are the most thoroughly characterized adult progenitor several differentiation models that may explain why donor- cells, mostly because of their easy accessibility and more derived bone marrow (BM) or peripheral blood (PB) than 30 years of experience with their clinical use for cells are found in recipient solid organ-specific tissue. It is transplantation to treat malignant disease. also conceivable that each solid organ tissue has its own circulating stem cells (eg, hematopoietic stem cells, angio- 4 Transdifferentiation of adult hematopoietic stem cells blasts, mesenchymal stem cells). Jiang et al identified and isolated a BM-derived multipotent adult progenitor cells The concept of adult stem cells being restricted to their own capable of differentiating in vivo into the hematopoietic tissue has been challenged over the past 5 years by lineage and into the epithelium of the liver, lung, and gut 4 numerous reports that adult stem cells can jump lineage when transplanted. Another possible explanation for barriers and differentiate into cells outside their own tissue, lineage plasticity is the de-differentiation of terminally a process called stem cell transdifferentiation. Many such differentiated cells to regain stem-like characteristics before 5 studies are based on a sex-mismatched hematopoietic stem the cells differentiate into another lineage. The stem cell transdifferentiation model has also been challenged. Cell fusion bypassing stem cell differentiation Correspondence: Dr M Ko¨ rbling, Department of Blood and Marrow has been postulated as an alternative mechanism to explain Transplantation, The University of Texas M. D. Anderson Cancer the presence of BM-derived cells in solid organ-specific Center, 1515 Holcombe Boulevard, Unit 423, Houston, TX 77030, USA tissue. In two separate studies, BM and brain cells have Adult stem cells and tissue repair MKo¨rbling et al S24 been shown to fuse spontaneously with embryonic stem Therapeutic strategies involving the differentiation poten- cells in vitro to adopt subsequently the phenotype of the tial of BM- or PB-derived stem cells to generate solid organ- recipient cells.6,7 However, the in vitro culture conditions specific tissue are hypothetical. One may speculate that solid to which those cells were exposed were far from being organ tissue damage triggers endogenous stem cells (eg, oval physiologic. Fused hybrid cells are characterized by cells, intestinal crypt cells) to undergo differentiation as the hyperdiploid DNA content, which is not regularly seen in first line of defense. In case the tissue-intrinsic stem cell pool stem cell differentiation experiments. Finally, the frequency is exhausted as a result of more extensive tissue damage, of cell fusion is very rare, approximately 3 logs less than the exogenous and circulating stem cells are recruited as a frequency of donor-derived BM or PB cells appearing in backup system to support local tissue repair. Two mechan- solid organ-specific tissue. Another mechanism refers to isms may act as triggers for cellular repair: (1) the horizontal DNA transfer originating from apoptotic cells microenvironment at the site of tissue damage by releasing that could result in the appearance of donor-derived DNA adhesion molecules and cytokines, and (2) an increase in the fragments in solid organ tissue.8 concentration of stem cells at the site of tissue damage. On a clinical level, study designs are obviously much more restricted in their ability to provide proof of stem cells originating from hematopoietic tissue and differentiating Conclusion into nonlymphohematopoietic tissue. In an allogeneic sex-mismatched transplant setting, BM-derived cells were We are confirming initial observations of developmental found to contribute to hepatocyte and cholangiocyte stem cell plasticity or stem cell differentiation mechanisms. formation at frequencies of up to 43 and 38%, respec- Currently the frequency of BM- or PB-derived nonlympho- tively.9 Alison’s group reported similar findings although at hematopoietic cells in solid organ tissue is too low to have somewhat lower frequencies.10 any clinical impact. Only after stem cell differentiation Since PB is the only link between BM-derived cells and mechanisms are fully understood can promising treatment solid organ-specific tissue, it was a logical further step to strategies be designed to redirect BM or PB stem cells to investigate the possibility of PB-derived cells generating generate solid organ tissue in a clinically relevant manner. nonlymphohematopoietic tissue. Orlic’s group successfully demonstrated the repair of infarcted heart tissue in a mouse References model by an increase in the concentration of circulating 11 stem cells. In a clinical setting, we recently reported the 1 Krause DS, Theise ND, Collector MI et al. Multi-organ, presence of XY-positive hepatocytes and epithelial cells of multi-lineage engraftment by a single bone marrow-derived the skin and gastrointestinal tract in five female recipients stem cell. Cell 2001; 105: 369–377. of rhG-CSF-mobilized, PB stem cell allografts from male 2 Lagasse E, Connors H, Al-Dhalimy M et al. Purified donors. Donor-derived, nonlymphohematopoietic cells hematopoietic stem cells can differentiate into hepatocytes were identified at frequencies ranging from 0 to 7% in the in vivo. Nat Med 2000; 6: 1229–1234. skin, gut, and liver of all five stem cell recipients. XY probe- 3 Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little positive cells were detected in liver tissue in these female evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002; 297: 2256–2259. recipients as early as day 13 and as late as day 354after 4Jiang Y, Jahagirda BN, Reinhardt RL et al. Pluripotency of transplantation. Engraftment of nonlymphohematopoietic mesenchymal stem cells derived from adult marrow. Nature cells did not seem to depend on tissue damage induced by 2002; 418: 41–49. graft-versus-host disease.12 5 Odelberg SJ, Kollhoff A, Keating MT. Dedifferentiation of In a similar experimental setting, donor-derived Y mammalian myotubes induced by msx1. Cell 2000; 103: 1099–1109. chromosome-positive and cytokeratin-positive keratino- 6 Terada N, Hamazaki T, Oka M et al. Bone marrow cells adopt cytes were found at frequencies ranging from 3.7 to the phenotype of other cells by spontaneous cell fusion. Nature 14.8% in six patients who underwent sex-mismatched PB 2002; 416: 542–545. stem cell transplantation. However, when the same 7 Ying QL, Nichols J, Evans E, Smith AG. Changing potency by Nature epidermal skin cells were cultured over 18–32 days through spontaneous fusion. 2002; 416: 545–548. 8 Garcia-Olmo D, Garcia-Olmo DC, Ontanon J, Martinez E. multiple passages to eliminate any contaminating lympho- Horizontal transfer of DNA and the ‘genometastasis hypo- hematopoietic cells, donor-derived Y chromosome-specific thesis’. Blood 2000; 95: 724–725. sequences could not be detected using the polymerase chain 9 Theise ND, Nimmakayalu M, Gardner R et al. Liver from reaction method. One may speculate that the Y chromo- bone marrow in humans. Hepatology 2000; 32: 11–16. some-specific sequences had been lost after several culture 10 Alison MR, Poulsom R, Jeffery R et al. Hepatocytes from passages or that the donor cells had no or reduced non-hepatic adult stem cells. Nature 2000; 406: 257. proliferative capability in vitro.13 11 Orlic D, Kajstura J, Chimenti S et al. Mobilized bone marrow Based on the morphological identification of XY cells repair the infracted heart, improving function and chromosome containing BM- or PB-derived solid organ- survival. Proc Natl Acad Sci USA 2001; 98: 10 344–10 349. et al specific cells, the frequency of those nonlymphohemato- 12 Ko¨ rbling M, Katz RL, Khanna A . Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood poietic cells is in the range of 10% or less. It is hypothesized stem cells. N Engl J Med 2002; 346: 738–746. that tissue damage may trigger BM- or PB-derived cells to 13 Hematti P, Sloand EM, Carvallo CA et al. Absence of donor- undergo differentiation into solid organ-specific tissue. The derived keratinocyte stem cells in skin tissue cultured from distribution pattern of those cells seems to be random, patients after mobilized peripheral blood hematopoietic stem although small clusters are sometimes found. cell transplantation. Exp Hematol 2002; 30: 943–-949.

Bone Marrow Transplantation