An analysis prepared for the Committee on Establishing a National Cord Blood Stem Cell Bank.

Margaret A. Goodell

Associate Professor

Center for Cell and Gene Therapy

Baylor College of Medicine

One Baylor Plaza, BCMN 505

Houston, TX 77098


Regeneration of nonhematopoietic tissues using hematopoietic stem cells has been a focus of research over the past 5 years, with the hope that the application of bone marrow and cord blood transplantation could be greatly expanded. However, basic research in this area has been controversial, and many reports are contradictory. A consensus view is emerging that progeny of hematopoietic stem cells can indeed become incorporated into nonhematopoietic tissue, but that this occurs with extremely low efficiency, and via a cell fusion mechanism, likely between myeloid and nonhematopoietic

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program D COMMISSIONED PAPER POTENTIAL NONHEMATOPOIETIC USES FOR STEM CELLS IN CORD BLOOD An analysis prepared for the Committee on Establishing a National Cord Blood Stem Cell Bank. Margaret A. Goodell Associate Professor Center for Cell and Gene Therapy Baylor College of Medicine One Baylor Plaza, BCMN 505 Houston, TX 77098 ABSTRACT Regeneration of nonhematopoietic tissues using hematopoietic stem cells has been a focus of research over the past 5 years, with the hope that the application of bone marrow and cord blood transplantation could be greatly expanded. However, basic research in this area has been controversial, and many reports are contradictory. A consensus view is emerging that progeny of hematopoietic stem cells can indeed become incorporated into nonhematopoietic tissue, but that this occurs with extremely low efficiency, and via a cell fusion mechanism, likely between myeloid and nonhematopoietic

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program tissues. The low efficiency indicates that, in the short-term, bone marrow and cord blood transplantation are unlikely to be optimal sources for regeneration of nonhematopoietic tissues. However, a number of strategies are being developed to improve the efficiencies with the long-term aim of using hematopoietic cell sources in therapy of nonhematopoietic disease. INTRODUCTION The stem cell field has witnessed an explosion of interest in the past 5 years, due to the tandem discoveries of human embryonic stem (hES) cells and reports of the potentially broad differentiation capacity of adult stem cells. In particular, the differentiation capacity of hematopoietic stem cells (HSC), primarily derived from the bone marrow (BM), has been a focus of interest. If, indeed, HSC can differentiate outside of hematopoietic lineages, then BM or cord blood (CB) transplantation could potentially be used for therapeutic applications far beyond those currently used, which are almost exclusively hematologic disorders. In this analysis, I will discuss the evidence for and against the concept that HSC may generate nonhematopoietic tissues. At this point in time, the literature in this general area is extensive. I will not attempt to review it comprehensively, as there are a number of excellent reviews in the field. Instead, I will endeavor to concisely summarize the data, using a few key papers as examples for the field. Because the majority of the work has been performed with HSC derived from BM, these will be the basis of the majority of the discussion. However, I will also discuss possible differences between BM- and cord CB-derived HSCs toward the end of this appendix. POTENTIAL NONHEMATOPOIETIC DIFFERENTIATION FROM BONE MARROW CELLS After Bone Marrow Transplantation One of the first reports to suggest that hematopoietic cells could generate nonhematopoietic tissue came from the observation that when a whole BM transplant was given to lethally irradiated recipient mice, and skeletal muscles of those animals were subsequently acutely injured, donor-derived cell nuclei were found incorporated into the regenerated skeletal muscle at a frequency of around 0.01 percent [1]. The donor BM was derived from a transgenic mouse strain that expressed lacZ under a nuclear-localized muscle-specific promotor, and the evidence for bona fide incorporation of BM cells into differentiated skeletal muscle was extremely convincing. A number of other studies, using BM transplants in mice, rats, and humans,

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program similarly indicated that donor-derived cells could be found in such diverse tissues as heart, liver, gut, brain (Table D-1). While the cumulative evidence suggested some degree of nonhematopoietic differentiation from some BM-derived cell, the prevalence of these so-called “transdifferentiation” events varied sometimes by two to three orders of magnitude (Table D-1), and the markers used to track BM progeny and the photomicroscopy evidence presented were not always equally persuasive. In addition, almost all of the initial studies involved transplantation of whole BM, leaving open the possibility that generation of nonhematopoietic progeny was derived from any number of cell types present in the BM, including potentially mesenchymal stem cells, differentiated hematopoietic cells, or conceivably tissue-specific stem cells “lost” in the BM. Nonhematopoietic Differentiation from HSCs In order to refine these observations and determine whether HSCs or their direct progeny were contributing to these diverse tissue types or whether a nonhematopoietic (circulating?) stem cell within BM was involved, several groups examined the engraftment activity of small numbers of purified HSCs. HSC preparations of 30 to 2000 cells were transplanted into recipients and shown to generate, in addition to peripheral blood, skeletal muscle cells [2], cardiac muscle and endothelial cells [3] and hepa- TABLE D-1 Donor Cell Contribution to Nonhematopoietic Tissues After Whole Bone Marrow Transplantation in Animal Models Species Target Tissue Approximate Frequency (%) Reference Mouse Macro and Microglia 0.5–2 [34]   Skeletal muscle Minimal [35]   Skeletal, cardiac muscle Not given [36]   Skeletal muscle 3.5 [16]   Endothelial cells Not given [37]   Neurons 0.2–0.3 [38]   Neurons 0.3–2.3 [39]   Neurons 0 [21]   Hepatocytes 2.2 [40] Dogs Endothelial cells n/a [41] Rat Oval cells/hepatocytes 0.14 [42]

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program tocytes [4]. The caveat to all of these studies is that even these highly purified populations could have included multiple stem cells: some stem cells in the preparations could have accounted for the hematopoietic activity, while other stem cells, or impurities, could have accounted for the nonhematopoietic activity. Thus, the next refinement was to examine generation of nonhematopoietic progeny from HSC at a clonal level, to determine whether one cell could generate both hematopoietic and nonhematopoietic progeny in the same animal. This has begun to be addressed. After BM transplantation with single HSC, extremely rare donor-derived hepatocytes and Purkinje cells were observed [5]. The generation of endothelial cells from single transplanted HSC was reported in a retinal neovascularization model using single HSC marked with green fluorescent protein (GFP) fluorescence [6]. And, in principle, this was examined in epithelial tissues, where HSCs transplanted by limiting dilution were shown to generate epithelial cells in liver, lung, and gut [7]. Surprisingly, in lung, HSC-donor progeny, tracked using in situ hybridization to donor Y-chromosome-positive cells in female recipients, were reported to generate nearly 20 percent of pneumocytes. While in a landmark paper, these data are not widely accepted, although a plausible alternative explanation (other than as technical artifacts) for the data has never been put forth, and the authors are well respected and have vigorously supported their claims. More recently, additional studies with single HSC transplantation have shown that HSC progeny can become incorporated into regenerating skeletal muscle both after acute injury and when transplanted into genetic models of skeletal muscle degeneration (specifically, the mdx mouse, a model of Duchene muscular dystrophy) [8], and of liver regeneration [9]. In both of these studies, the incorporation of HSC-progeny into the tissues was an exceedingly rare event (around 0.03 percent of recipient cell nuclei in the given tissue). However, in the liver, a powerful selection system, in a mouse model of familial tyrosinemia, allowed HSC-derived hepatocytes to repopulate up to around a third of the liver. Moreover, the HSC-derived hepatocytes provided full function and rescued the mice from an otherwise lethal condition. These data unequivocally showed that HSC progeny could become incorporated into nonhematopoietic tissues, albeit at a low efficiency. Human Transplantation Data In addition to the studies in animal models, a number of groups have looked at clinical specimens for evidence of similar “plasticity” of cells derived from human BM. All of these studies used samples from patients with organ or BM transplants that were sex mismatched (Table D-2). For

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program TABLE D-2 Circulating Cell Contribution to Nonhematopoietic Tissues in Clinical Specimens Tissue Transplanted Donor Cells Observed Approximate Frequency (%) Reference Bone marrow Osteoblasts 1.5–2 [43] Bone marrow Hepatocytes 2.2 [10] Bone marrow GI tract epithelia 0–4.6 [14] Bone marrow Stroma 0 [19] Mobilized peripheral blood Keratinocytes 0 [20] Mobilized peripheral blood Hepatocytes 0–7 [15]   GIa tract and skin epithelia 0–7 [15] Heart Cardiomyocytes 20 [12]   Endothelium 15 [12] Heart Cardiomyocytes 0.04 [11]   Endothelium 25 [11] Heart Cardiomyocytes 0.2 [13] Heart Cardiomyocytes 0 [18] Heart Cardiomyocytes 0 [17] aGI = gastrointestinal NOTE: In the BM or peripheral blood transplants, male donor cells were transplanted into female recipients. In the heart transplants, female hearts were transplanted into male recipients. example, hearts from females transplanted into males that showed evidence of male-derived cardiomyocytes or endothelial cells suggest that circulating male cells (potentially derived from BM) could give rise to these cell types. Likewise, in patients who had sex-mismatched BM transplants, the contribution of the donors’ cells to nonhematopoietic organs could be assessed. When tissue specimens from such patients have been examined using in situ hybridization for the Y chromosome, evidence of chimerism was found in multiple cell types, including hepatocytes [10], cardiomyocytes [11–13], and skin and gut epithelium [14, 15]. While the data imply that a circulating cell is engrafting into nonhematopoietic tissues, the data do not demonstrate that the phenomenon is related to the stem cell, nor even that the donor cell is restricted to the hematopoietic lineage, since many cell types could potentially circulate to some degree. Furthermore, in situ hybridization for the Y chromosome is not the most reliable technique; so, while the data are important, they are not all widely accepted.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program Prevalence of “Transdifferentiation” While the animal model and clinical data suggest that HSCs can generate nonhematopoietic cells, one of the major discrepancies of the field is the wide variance reported in the prevalence of such events. For example, in studies of BM-derived engraftment into the heart, the reported frequencies of engraftment vary by four orders of magnitude—a difference that in itself raises serious concerns about the technologies used and the conclusions drawn. In three studies where male Y-chromosome-positive host cells were followed in recipients of female heart allografts, one group reported that up to 20 percent of cardiomyocytes were host-derived [12], one group reported that 0.2 percent were host-derived [13], and one group that 0.04 percent were host derived [11]. This final figure is closest to that seen in similar studies in the mouse using the lacZ marker, where engraftment was observed to be around 0.02 percent [3]. Likewise, frequencies of BM-derived engraftment into skeletal muscle in mouse models vary by three orders of magnitude in the literature, from 0.01 percent [1] to over 3 percent [16]. Variations in engraftment frequencies could be due to a variety of factors, such as duration of the graft, tissue type, or degree of graft versus host disease (GVHD). Indeed, it was observed that the level of cardiomyocyte engraftment correlated with the degree of GVHD within a group of patients [12]. However, GVHD would also bring higher numbers of BM-derived inflammatory cells into affected tissues, which, when closely adhered to the target tissue, could potentially be mistaken for “transdifferentiation” events. Lack of Engraftment Also Reported Some laboratoriess have looked for BM-derived contribution to specific tissues and failed to see it at all. Two groups have looked in human specimens for BM-derived engraftment in human cardiomyocytes and failed to observe any [17, 18]. Karotinocyte stem cells and stromal cells were not found to be generated from the BM in clinical specimens [19, 20]. And in the mouse, attempts to observe neural differentiation from BM cells failed in some studies [21]. Also in the mouse, when marked hematopoietic cells were introduced via a parabiotic mouse model, no engraftment into any tissue was observed [5], although for most tissues, no injuries were induced, which is thought to play an important role in recruitment and differentiation of stem cells. Mechanism of HSC-Derived Incorporation in Nonhematopoietic Tissue In the most recent studies using single transplanted HSCs, the mechanism of HSC-derived incorporation was also examined, and this has direct bearing on the potential therapeutic use of BM and CB for nonhemato-

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program poietic disease. Work with embryonic stem cells had suggested the possibility that cell-cell fusion events could be accounting for some of the apparent “transdifferentiation” of adult stem cells into new tissue types [22, 23]. Using lineage tracing strategies, fusion between hematopoietic cells and nonhematopoietic regenerating target tissue has now been shown to be a likely mechanism explaining at least some incorporation of HSC-progeny into liver and skeletal muscle [8, 9]. Moreover, it is likely that the fusogenic cell is not a circulating HSC, but, instead, a myeloid cell, most likely a macrophage, derived from the HSCs [9, 24]. This interpretation of the data has to be further corroborated, and extended to other tissues, but is now becoming a prevailing view in the field. SUMMARY OF EVIDENCE Overall, the evidence overwhelmingly indicates that HSC-derived cells can, at least at low levels, become incorporated in nonhematopoietic tissues. Most studies, however, indicate that this occurs with extremely low efficiency, far too low to likely be of therapeutic benefit in most disease states. Moreover, these studies have shown that injury of the target tissue is essential for incorporation. Finally, the recent studies showing that the majority of incorporation is due to fusion with HSC progeny, most likely with a myeloid cell, appear to be widely accepted, and a number of investigators are using these concepts as a basis to harness the phenomenon for development of therapeutic modalities (see below). The end result is that incorporation of the HSC-derived nuclei into regenerating nonhematopoietic tissue can indeed occur. The HSC-derived cells are essentially donating a wild-type genome, via fusion, to the recipient tissue. In the case of the mdx mouse, rare muscle fibers, previously negative for the dystrophin protein (lacking in Duchene muscular dystrophy), could be identified which now expressed the wild-type protein [8]. In the case of the mouse model for familial tyrosinemia, a severe liver disease, selection for the rare HSC-incorporation events enabled a complete “cure” of this otherwise fatal disease [9, 24], a truly remarkable result of cell-cell fusion. These studies, while not leaving a clear path toward therapeutic application of the phenomenon (see below), do justify some of the initial excitement for the concept of using BM or CB for therapy of nonhematopoietic disease. Nevertheless, serious caution, in the face of the major discrepancies in efficiencies and mechanisms is also warranted. Major Discrepancies Cloud the Field While I have described a consensus view, there is no doubt that this field remains highly polarized with other conflicting opinions. There are

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program several excellent laboratories that have published their findings recently in high-profile journals that contradict the idea that the phenomenon is rare [7, 16], due to fusion [25, 26], requires severe injury (other than BM transplantation) [7, 16], or involves a differentiated myeloid cell [27]. Furthermore, clinical studies of BM cell infusion into infarcted hearts are reporting modest improvements in function [28–30], even though animal studies are unable to show functional improvements using similar strategies, and show no evidence that BM-derived cells are even incorporated into the injured hearts at appreciable frequencies [31, 32]. IMPLICATIONS FOR CELL THERAPY USING CB OR BM TRANSPLANTATION With the inefficiencies that I have described, we are unlikely to be able to use, at this time, BM or CB transplantation broadly for treatment of nonhematopoietic diseases. Diseases such as muscular dystrophy would very likely require contribution of wild-type cells to muscle at much higher levels than 0.05 percent or so of all nuclei. Likewise, most liver diseases are not amenable to selection for the rare HSC-liver incorporation events, preventing immediate application of BM transplantation for most liver diseases. These are clear limitations with the existing technology. However, it is possible that the efficiency of incorporation could be improved, and several laboratories are investigating this. How to improve the efficiency depends on the major bottlenecks, which are currently poorly understood but likely include some of the following. First, tissues that tolerate a polyploid state are likely to be the best targets. Skeletal muscle, for example, exists as a syncitium, and is postmitotic. Therefore, fusion of a nonhematopoietic cell into a muscle fiber is unlikely to cause deleterious events downstream, such as neoplastic transformation. Likewise, hepatocytes typically persist as highly polyploid cells, and this does not appear to affect their function or regenerative capacity. Second, cell-cell fusion is likely an inefficient process. Strategies to improve the efficiency of fusion, particularly in a manner targeted to specific cell types, may enhance the usefulness of the technology. The technology then becomes one of a gene delivery strategy using a hematopoietic cell to provide a wild-type or otherwise therapeutic gene. Third, once cells fuse, the interactions between the different cellular programs are completely unexplored. Presumably, the entire muscle program needs to be activated in a macrophage that is fusing with a muscle fiber, in order to activate muscle-specific and therapeutic genes from the macrophage genome. The efficiency of this reprogramming and potential strategies to manipulate or bias it are not understood. Finally, if macrophages are indeed the only cell type that mediates these fusion events, strategies based on macrophage transplantation, rather than whole

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program BM or CB, could prevail. These research areas could certainly bear fruit and lead to the expanded application of BM or CB transplantation for therapy of nonhematopoietic disease, but this is likely a long-term prospect. What Needs to Be Established to Determine Usefulness of CB in Nonhematopoietic Repair? As stated above, with current data and discrepancies in the field, it is difficult to definitively argue that BM or CB transplantation could not be used for therapy of nonhematopoietic disease, although in my opinion this will not be feasible in the short term. What needs to be established to answer this more definitively? Some of the discrepancies in the field are due to poor-quality studies. Therefore, additional clonal analyses such as those described above with muscle and liver, and tracking of cells with ideal markers need to be performed. Better evaluation of the potential of human cells is needed. Unfortunately, there is an enormous gap in the ability to test the potential of human cells due to lack of good animal models that will support the growth of human cells. It is possible that data from other large animal models could assist. Finally, if the efficiency of HSC-derived incorporation could be improved, using excellent models and markers, with some of the strategies mentioned above, the therapeutic usefulness of hematopoietic cell transplantation may increase. ARE THERE DIFFERENCES BETWEEN STEM CELLS IN CORD BLOOD AND BONE MARROW? There is a wide perception in the lay press, and even among scientists not expert in the field, that stem cells in CB are somehow more primitive than those in BM. To some extent, this view is currently being exploited in the advertising from the private CB banking companies to persuade parents to bank their baby’s CB in order to have the potential to generate a wide variety of tissues. While there is certainly some weak support for this notion in the literature, this view is not widely supported by most clinical hematologists. The HSC in CB may be more plentiful than those in adult blood. CB is certainly a source enriched for HSCs, but there is little or no convincing evidence that CB contains any “embryonic” stem cell that has a differentiation capacity beyond that of normal BM HSCs. CB has been reported to contain mesenchymal-like stem cells [33], that could conceivably have some broad differentiative potential, but this remains to be substantiated by additional laboratories, and such cells are unlikely to also have HSC potential. Furthermore, there is little evidence that any non-HSC type is capable of reaching wide distribution via the circulation. This area could certainly

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program benefit from some additional high quality research, but at this point, the prevailing view among basic HSC biologists as well as clinicians is that there is no significant difference between CB and BM that would warrant a special focus on CB as a source of nonhematopoietic stem cell potential. SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS As indicated above, in my opinion, it appears unlikely at this point that wholesale replacement or repair of nonhematopoietic tissues by circulating stem cells in CB or BM is possible; nevertheless, there is not complete consensus in the field. With the current observed inefficiencies and uncertainties, it is difficult to use the potential for nonhematopoietic differentiation as a justification for a national CB banking program for the short-term. Of course, the advent of new technologies, which a number of laboratories are actively working toward, could change this potential. In addition, one might envision that if regeneration of nonhematopoietic cells from HSCs were improved to the point that hematopoietic transplantation could be used as a therapeutic modality for treatment of nonhematopoietic disease, gene-engineered autologous HSC sources would likely be favored over allogeneic banked sources. REFERENCES 1. Ferrari, G., G. Cusella-De Angelis, M. Coletta, E. Paolucci, A. Stornaiuolo, G. Cossu, and F. Mavilio (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279: 1528–30. 2. Gussoni, E., Y. Soneoka, C.D. Strickland, E.A. Buzney, M.K. Khan, A.F. Flint, L.M. Kunkel, and R.C. Mulligan (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401: 390–4. 3. Jackson, K.A., S.M. Majka, H. Wang, J. Pocius, C.J. Hartley, M.W. Majesky, M.L. Entman, L.H. Michael, K.K. Hirschi, and M.A. Goodell (2001) Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107: 1395–402. 4. Lagasse, E., H. Connors, M. Al-Dhalimy, M. Reitsma, M. Dohse, L. Osborne, X. Wang, M. Finegold, I.L. Weissman, and M. Grompe (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6: 1229–34. 5. Wagers, A.J., R.I. Sherwood, J.L. Christensen, and I.L. Weissman (2002) Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297: 2256–9. 6. Grant, M.B., W.S. May, S. Caballero, G.A. Brown, S.M. Guthrie, R.N. Mames, B.J. Byrne, T. Vaught, P.E. Spoerri, A.B. Peck, and E.W. Scott (2002) Adult hematopoietic stem cells provide functional hemangioblast activity during retinal neovascularization. Nat Med 8: 607–12. 7. Krause, D.S., N.D. Theise, M.I. Collector, O. Henegariu, S. Hwang, R. Gardner, S. Neutzel, and S.J. Sharkis (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105: 369–77.

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