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Hal E. Broxmeyer - One of the best experts on this subject based on the ideXlab platform.

  • High-efficiency recovery of functional hematopoietic progenitor and stem cells from human cord blood cryopreserved for 15 years.
    Proceedings of the National Academy of Sciences, 2003
    Co-Authors: Hal E. Broxmeyer, Scott Cooper, Giao Hangoc, Edward F. Srour, Stacie A. Anderson, David M. Bodine
    Abstract:

    Transplanted cord blood (CB) hematopoietic stem cells (HSC) and progenitor cells (HPC) can treat malignant and nonmalignant disorders. Because long-term cryopreservation is critical for CB banking and transplantation, we assessed the efficiency of recovery of viable HSC/HPC from individual CBs stored frozen for 15 yr. Average recoveries (± 1 SD) of defrosted nucleated cells, colony-forming unit-granulocyte, -macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), and colony-forming unit-granulocyte, -erythrocyte, -monocyte, and -megakaryocyte (CFU-GEMM) were, respectively, 83 ± 12, 95 ± 16, 84 ± 25, and 85 ± 25 using the same culture conditions as for prefreeze samples. Proliferative capacities of CFU-GM, BFU-E, and CFU-GEMM were intact as colonies generated respectively contained up to 22,500, 182,500, and 292,500 cells. Self-renewal of CFU-GEMM was also retained as replating efficiency of single CFU-GEMM colonies into 2° dishes was >96% and yielded 2° colonies of CFU-GM, BFU-E, and CFU-GEMM. Moreover, CD34+CD38− cells isolated by FACS after thawing yielded >250-fold ex vivo expansion of HPC. To assess HSC capability, defrosts from single collections were bead-separated into CD34+ cells and infused into sublethally irradiated nonobese diabetic (NOD)/severe combined immunodeficient (SCID) mice. CD45+ human cell engraftment with multilineage phenotypes was detected in mice after 11–13 wk; engrafting levels were comparable to that reported with fresh CB. Thus, immature human CB cells with high proliferative, replating, ex vivo expansion and mouse NOD/SCID engrafting ability can be stored frozen for >15 yr, can be efficiently retrieved, and most likely remain effective for clinical transplantation.

  • Retroviral transfer of the recombinant human erythropoietin receptor gene into single hematopoietic stem/progenitor cells from human cord blood increases the number of erythropoietin-dependent erythroid colonies.
    Blood, 1996
    Co-Authors: Winnie W. Keeble, Hal E. Broxmeyer, David Kabat, Grover C. Bagby, Maureen E. Hoatlin
    Abstract:

    To test whether an enforced expression of a lineage-specific cytokine receptor would influence the proliferation/differentiation of hematopoietic stem/progenitor cells, retroviral vectors containing the human erythropoietin receptor (hEpoR) gene were used to transduce the hEpoR gene into phenotypically sorted subsets of cells. CD34 , CD34++CD33-, and CD34++CD33+ populations of human cord blood, highly enriched for hematopoietic stem/progenitor cells, were sorted and plated as single cells per well in methylcellulose culture medium containing early acting growth factors in the presence or absence of Epo. The hEpoR gene was efficiently transduced into single high proliferative potential colony-forming cells (HPP-CFC) and multipotential (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM]), erythroid (burst-forming unit-erythroid [BFU- E]), and granulocyte-macrophage (colony-forming unit-granulocyte- macrophage [CFU-GM]) progenitor cells. As expected in cultures grown in the absence of Epo, no BFU-E or CFU-GEMM colonies grew. In the presence of Epo, the hEpoR-gene transduced cells formed significantly more CFU- GEMM and BFU-E colonies than did the controls. A significant decrease in HPP-CFC colonies was also observed under these conditions. Little or no effect of hEpoR gene transduction was apparent in the numbers of CFU- GM colonies formed in the presence or absence of Epo. All of the above results were similar whether the cell populations assessed were CD34 or their CD33- or CD33+ subsets plated in the presence of growth factors at 200 cells/mL or after limiting dilution at 2 cells/well. These results suggest that the profile of detectable stem/progenitors can be altered by retrovirus-mediated expression of the hEpoR gene.

  • FLT3-LIGAND STIMULATES/COSTIMULATES THE GROWTH OF MYELOID STEM/PROGENITOR CELLS
    Experimental hematology, 1995
    Co-Authors: Hal E. Broxmeyer, S. Cooper, L. Ruggieri, S D Lyman
    Abstract:

    The present studies evaluated effects of recombinant human (rhu) and murine (rmu) flt3 ligand (flt3-L) on colony formation by subsets of myeloid stem and progenitor cells present in low-density (LD) and cell-sorted CD34 hu cord blood (CB) and bone marrow (BM) cells and unseparated mu BM cells. By itself, flt3-L had weak colony-stimulating activity. It stimulated small dispersed CFU-GM-type colonies, but not BFU-E, CFU-GEMM, or HPP-CFC colonies, from LD and CD34 huCB and BM. However, flt3-L had additive to greater-than-additive effects on colony number and size by CFU-GM stimulated with GM-CSF or IL-3, with or without Steel factor (SLF); by CFU-G stimulated by G-CSF with or without SLF; by CFU-M stimulated by CSF-1; and by BFU-E, CFU-GEMM, and HPP-CFC stimulated by Epo with or without IL-3 or SLF. Flt3-L enhanced the effects of SLF, alone and in combination with other CSFs. Similar effects were apparent on LD and sorted CD34 cells and also at the level of single sorted and isolated CD34 cells/well. Flt3-L enhanced expansion of immature subsets of huCD34(+)-column separated CB CFU-GM stimulated by the potent combination of SLF and PIXY321 (a GM-CSF/IL-3 fusion protein). While flt3-L did not enhance the replating capacity of CFU-GEMM plated in the presence of Epo and SLF, it enhanced numbers of these CFU-GEMM colonies with the capacity to be replated. Flt3-L effects were not species-specific; rhu and rmu forms were active on huCB/BM and muBM. These results demonstrate the potent direct-acting stimulating/costimulating activities of flt3-L in vitro on myeloid stem/progenitor cells.

  • Influence in vitro of IL-3/Epo fusion proteins compared with the combination of IL-3 plus Epo in enhancing the proliferation of single isolated erythroid and multipotential progenitor cells from human umbilical cord blood and adult bone marrow.
    Experimental hematology, 1995
    Co-Authors: Mang Xiao, Hal E. Broxmeyer, L. K. Jolliffe, S. Jones, N. Weich
    Abstract:

    Human interleukin-3/erythropoietin (IL-3/Epo) fusion protein have been constructed, expressed, and tested for biological activity. These fusion proteins were previously shown to be active on erythroid progenitors (BFU-E) from unseparated human bone marrow. We evaluated if these fusion proteins could stimulate erythroid and multipotential progenitor cells directly at the single-cell level. Two IL-3/Epo fusion proteins containing short (SL-3E, two amino acids) and long (LL-3E, 23 amino acids) linker sequences as well as a short linker Epo/IL-3 sequence (SL-E3, three amino acids) were tested. Highly enriched CD34 or BFU-E enriched CD34 CD33- cells from human umbilical cord blood or CD34 HLA-DR+CD33- cells from normal adult bone marrow were sorted as single cells into single wells. The combination of Epo plus IL-3 synergized to enhance the proliferation of BFU-E and multipotential progenitors (CFU-GEMM) in comparison to the individual effects of these cytokines. The three fusion proteins also enhanced proliferation of BFU-E and CFU-GEMM at the single-cell level and were at least as active as the combination of Epo and IL-3, demonstrating that IL-3/Epo fusion proteins directly stimulate proliferation of BFU-E and CFU-GEMM and that biological activity of IL-3 and Epo in vitro can be maintained when these proteins are fused. The activity of the combination of Epo and IL-3 or the fusion proteins was partially neutralized by preincubation with monoclonal antibodies to either Epo or IL-3 and was neutralized by greater than 90% by the combination of both antibodies, suggesting that the Epo and IL-3 components of the fusion proteins were both involved in the enhancing activity of these proteins. Additionally, use of monoclonal antibody to the human Epo receptor completely blocked the stimulating/enhancing activity of Epo alone, Epo plus IL-3, or the fusion proteins for stimulation of colony formation by BFU-E and CFU-GEMM but not for granulocyte-macrophage progenitors (CFU-GM), suggesting that the enhancing effects of the fusion proteins are most likely mediated, at least in part, by the Epo receptor.

  • CYTOKINE-DEPENDENT EX VIVO EXPANSION OF EARLY SUBSETS OF CD34+ CORD BLOOD MYELOID PROGENITORS IS ENHANCED BY CORD BLOOD PLASMA BUT EXPANSION OF THE MORE MATURE SUBSETS OF PROGENITORS IS FAVORED
    Blood cells, 1994
    Co-Authors: L. Ruggieri, S Heimfeld, Hal E. Broxmeyer
    Abstract:

    Expansion of stem/progenitor cells has important implications for transplantation. We recently reported that a factor or factors in cord blood (CB), but not adult peripheral blood (PB), plasma enhanced replating of granulocyte erythroid macrophage megakaryocyte colony-forming units (CFU-GEMM) progenitors, a measure of self-renewal capacity. In this context, we evaluated effects of CB plasma, in comparison with PB plasma and fetal bovine serum (FBS), on ex vivo expansion of CD34+ column-separated (72-98% CD34+) CB cells using stroma-free cultures in the absence and presence of either PIXY321 (a granulocyte-macrophage colony-stimulating factor/interleukin-3 [GM-CSF/IL-3] fusion protein), IL-3+IL-6+IL-1, or steel factor (SLF) -/+ PIXY. CB plasma, PB plasma, or FBS alone did not sustain cell numbers. Combinations of CB plasma +SLF+PIXY induced maximal cumulative nucleated cell expansion (1044-fold), which was greater than that of PB plasma plus cytokines (633-fold) and FBS plus cytokines (142-fold). Total CD34+ cells peaked by day 7 with 7-fold expansion in the presence of CB plasma+SLF+PIXY compared with PB plasma or FBS with these same cytokines (threefold each). By day 7, total CFU-GEMM production in the presence of either PIXY, SLF+PIXY, or IL-3+IL-6+IL-1 was greater with CB plasma (maximum 11.4-fold average increases) than with PB plasma (6.8-fold increase). These increases were greater than with FBS. However, PB plasma was at least as good as CB plasma for expansion of immature and mature subsets of CFU-GM. The frequency of progenitors decreased with time, and expansion was coupled with differentiation. Although the proliferative capacity of CFU-GEMM was maintained, the capacity of CFU-GEMM to be replated decreased after time in suspension culture, suggesting age-related commitment of cells. Moreover, with plasma +SLF+PIXY for 7 days, expansion of more mature CFU-GM (responsive to GM-CSF) was greater (16-146-fold with CB plasma and 31-208-fold with PB plasma) than immature CFU-GM (responsive to GM-CSF+SFL) (4- to 14-fold with CB plasma and 6- to 17-fold with PB plasma). The results suggest that CB plasma enhances expansion of CFU-GEMM to a greater extent than PB plasma or FBS, but expansion in these cultures favors more mature subsets of cells.

A. Ganser - One of the best experts on this subject based on the ideXlab platform.

  • Megakaryocyte differentiation capacity of human pluripotent bone marrow progenitor cells CFU‐GEMM in vitro after cryopreservation*
    Scandinavian Journal of Haematology, 2009
    Co-Authors: A. Ganser, D. Hoelzer
    Abstract:

    The effect of cryopreservation on the pluripotent haemopoietic progenitors CFU-GEMM as well as on the megakaryocytic (CFU-Mk), erythroid (BFU-E) and granulocytic-monocytic (CFU-GM) progenitor cells was analyzed. Progenitor cell recovery after freezing, as determined in 5 experiments, averaged 89% for CFU-GEMM (range: 63% - 194%), 85% for CFU-Mk (range: 62% - 96%), 92% for BFU-E (range: 43% - 174%) and 60% for CFU-GM (range: 31% - 93%). Immunological analysis of individual mixed colonies using a double labelling immunoalkaline phosphatase slide technique and monoclonal antibodies against megakaryocytic and granulocytic cells revealed megakaryocytic cells in more than 79% (range: 73% - 94%) and 84% (range: 75% - 87%) of mixed colonies before and after freezing, respectively. Our results indicate that cryopreservation of human bone marrow cells does not alter the megakaryocytic differentiation capacity of the haemopoietic progenitor cells CFU-GEMM and CFU-Mk in vitro.

  • Effect of recombinant human transforming growth factor beta and tumor necrosis factor alpha on bone marrow progenitor cells of HIV-infected persons
    Annals of Hematology, 1991
    Co-Authors: R. G. Geissler, D. Hoelzer, O. G. Ottmann, M. Eder, G. Kojouharoff, A. Ganser
    Abstract:

    With progressive disease, the majority of patients with human immunodeficiency virus (HIV) infection develop bone marrow failure with anemia, leukopenia, and thrombocytopenia, the cause of which has not yet been clarified. Besides direct infection of bone marrow progenitor cells and immune-mediated cytolysis, the action of inhibitory cytokines, like transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α), has to be discussed with regard to their pathophysiological role in HIV-induced bone marrow failure. Therefore, the influence of recombinant human TGF-β and TNF-α on colony growth of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells from the bone marrow of HIV-1-infected persons and normal controls was assessed in methylcellulose cultures. Both cytokines inhibited the colony formation of hematopoietic progenitor cells from HIV-positive persons. When added to unseparated bone marrow cells from HIV-infected persons and normal controls, the 50% inhibition (ID_50) of BFU-E by TGF-β occurred at 1.3 ng/ml and 3.7 ng/ml, respectively, while the ID_50 of CFU-GM occurred at 15.5 ng/ml and 142.7 ng/ml. Concentrations of TNF-α, causing 50% inhibition of colony formation by bone marrow cells from HIV-infected or noninfected individuals were 6.3 U/ml and 17.0 U/ml for BFU-E, and 24.4 U/ml and >3,000 U/ml for CFU-GM, respectively. The ID_50 of the CFU-GEMM growth was below the lowest concentration of both cytokines tested. The suppressive effects were specifically abolished by antibodies against TGF-β and TNF-α, thus confirming that the inhibitory activities were due to the cytokine preparation used.

Klaus Havemann - One of the best experts on this subject based on the ideXlab platform.

  • Storage of noncryopreserved periphered blood stem cells for transplantation
    Annals of Hematology, 1996
    Co-Authors: G. Hechler, Roy Van Der Weide, H. Köppler, Jochen Heymanns, Klaus Havemann
    Abstract:

    Mobilized peripheral blood stem cells (PBSC) were collected in autologous plasma and acid-citrate-dextrose formula A (ACD-A) by leukaphereses using the CS3000 cell separator (Baxter) and stored at 4°C in a refrigerator for 8 days. We have looked at the viability of the nucleated cells with the trypan blue test and the proliferation and differentiation capacity using a standardized progenitor cell cloning assay. The changes in viability, granulocyte-macrophage colonyforming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed-lineage colony-forming units (CFU-GEMM) were determined daily during the storage period. Viability was 90.8% (SD 8%) at day 0 and declined to a mean of 69.5% (SD 15.5%) at day 8. CFU-GM decreased to 47% (SD 28.7%), CFU-GEMM to 48% (SD 42.2%), and BFU-E to 40.1% (SD 18.4%) after 6 days. After 5 days of storage the mean viability was 79.7% (SD 17.8%), whereas the mean CFU-GM were 65.3% (SD 28.4%) the mean CFU-GEMM were 61.8% (SD 30.4%) and the mean BFU-E were 55.1% (SD 18.2%). At day 4 viability was still 82.5% (SD 17.0%), recovery of CFU-GM was 78.5% (SD 28.8%), recovery of CFU-GEMM was 70.7% (SD 40.4%) and recovery of BFU-E was 65.0% (SD 17.5%). These data show, that PBSC can be stored safely over at least 5 days at 4°C while the patient receives high-dose chemotherapy.

  • Storage of noncryopreserved periphered blood stem cells for transplantation
    Annals of Hematology, 1996
    Co-Authors: G. Hechler, Roy Van Der Weide, H. Köppler, Jochen Heymanns, Klaus Havemann
    Abstract:

    Mobilized peripheral blood stem cells (PBSC) were collected in autologous plasma and acid-citrate-dextrose formula A (ACD-A) by leukaphereses using the CS3000 cell separator (Baxter) and stored at 4°C in a refrigerator for 8 days. We have looked at the viability of the nucleated cells with the trypan blue test and the proliferation and differentiation capacity using a standardized progenitor cell cloning assay. The changes in viability, granulocyte-macrophage colonyforming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed-lineage colony-forming units (CFU-GEMM) were determined daily during the storage period. Viability was 90.8% (SD 8%) at day 0 and declined to a mean of 69.5% (SD 15.5%) at day 8. CFU-GM decreased to 47% (SD 28.7%), CFU-GEMM to 48% (SD 42.2%), and BFU-E to 40.1% (SD 18.4%) after 6 days. After 5 days of storage the mean viability was 79.7% (SD 17.8%), whereas the mean CFU-GM were 65.3% (SD 28.4%) the mean CFU-GEMM were 61.8% (SD 30.4%) and the mean BFU-E were 55.1% (SD 18.2%). At day 4 viability was still 82.5% (SD 17.0%), recovery of CFU-GM was 78.5% (SD 28.8%), recovery of CFU-GEMM was 70.7% (SD 40.4%) and recovery of BFU-E was 65.0% (SD 17.5%). These data show, that PBSC can be stored safely over at least 5 days at 4°C while the patient receives high-dose chemotherapy.

D. Hoelzer - One of the best experts on this subject based on the ideXlab platform.

  • Megakaryocyte differentiation capacity of human pluripotent bone marrow progenitor cells CFU‐GEMM in vitro after cryopreservation*
    Scandinavian Journal of Haematology, 2009
    Co-Authors: A. Ganser, D. Hoelzer
    Abstract:

    The effect of cryopreservation on the pluripotent haemopoietic progenitors CFU-GEMM as well as on the megakaryocytic (CFU-Mk), erythroid (BFU-E) and granulocytic-monocytic (CFU-GM) progenitor cells was analyzed. Progenitor cell recovery after freezing, as determined in 5 experiments, averaged 89% for CFU-GEMM (range: 63% - 194%), 85% for CFU-Mk (range: 62% - 96%), 92% for BFU-E (range: 43% - 174%) and 60% for CFU-GM (range: 31% - 93%). Immunological analysis of individual mixed colonies using a double labelling immunoalkaline phosphatase slide technique and monoclonal antibodies against megakaryocytic and granulocytic cells revealed megakaryocytic cells in more than 79% (range: 73% - 94%) and 84% (range: 75% - 87%) of mixed colonies before and after freezing, respectively. Our results indicate that cryopreservation of human bone marrow cells does not alter the megakaryocytic differentiation capacity of the haemopoietic progenitor cells CFU-GEMM and CFU-Mk in vitro.

  • Effect of recombinant human transforming growth factor beta and tumor necrosis factor alpha on bone marrow progenitor cells of HIV-infected persons
    Annals of Hematology, 1991
    Co-Authors: R. G. Geissler, D. Hoelzer, O. G. Ottmann, M. Eder, G. Kojouharoff, A. Ganser
    Abstract:

    With progressive disease, the majority of patients with human immunodeficiency virus (HIV) infection develop bone marrow failure with anemia, leukopenia, and thrombocytopenia, the cause of which has not yet been clarified. Besides direct infection of bone marrow progenitor cells and immune-mediated cytolysis, the action of inhibitory cytokines, like transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α), has to be discussed with regard to their pathophysiological role in HIV-induced bone marrow failure. Therefore, the influence of recombinant human TGF-β and TNF-α on colony growth of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells from the bone marrow of HIV-1-infected persons and normal controls was assessed in methylcellulose cultures. Both cytokines inhibited the colony formation of hematopoietic progenitor cells from HIV-positive persons. When added to unseparated bone marrow cells from HIV-infected persons and normal controls, the 50% inhibition (ID_50) of BFU-E by TGF-β occurred at 1.3 ng/ml and 3.7 ng/ml, respectively, while the ID_50 of CFU-GM occurred at 15.5 ng/ml and 142.7 ng/ml. Concentrations of TNF-α, causing 50% inhibition of colony formation by bone marrow cells from HIV-infected or noninfected individuals were 6.3 U/ml and 17.0 U/ml for BFU-E, and 24.4 U/ml and >3,000 U/ml for CFU-GM, respectively. The ID_50 of the CFU-GEMM growth was below the lowest concentration of both cytokines tested. The suppressive effects were specifically abolished by antibodies against TGF-β and TNF-α, thus confirming that the inhibitory activities were due to the cytokine preparation used.

He Broxmeyer - One of the best experts on this subject based on the ideXlab platform.

  • Enhancement of proliferation and differentiation of erythroid progenitors by co-transduction of erythropoietin receptor and H-ras cDNAs into single CD34^3+ cord blood cells
    Bone Marrow Transplantation, 2000
    Co-Authors: L Lu, Z.h. Li, Y. Ge, He Broxmeyer
    Abstract:

    Our previous studies have demonstrated that retrovirus-mediated gene transduction of either the human erythropoietin receptor (EpoR) or H-ras cDNA into single purified hematopoietic progenitor (HPC), CD34^3+, cells from cord blood (CB) resulted in increased numbers and sizes of erythroid cell containing colonies. We therefore evaluated if there were further effects when H-ras and EpoR genes were co-transduced into the same progenitor cells. Highly purified single sorted CD34^3+ CB cells were transduced with retroviral vectors encoding EpoR or H-ras cDNA. At the single cell level, and in response to stimulation by a combination of growth factors, including Epo, the number of colonies formed by BFU-E and CFU-GEMM was significantly increased in cells transduced with either single H-ras or EpoR cDNA compared to mock virus-transduced cells as previously described. Increased numbers of BFU-E, but not CFU-GEMM, colonies were produced from cells simultaneously co-transduced with both EpoR and H-ras genes. Little or no growth was seen in transduced cells without exogenously added cytokines. The size of all types of colonies including CFU-GM was increased in cells transduced with H-ras and/or EpoR cDNAs, and the greatest increase was noticed in cells co-transduced with both genes. Integration and expression of either gene in individual colonies as assessed by PCR and RT-PCR analysis were 45–62% and 48–58%, respectively, with approximately 31% of the cells containing and expressing both genes. These results add to information suggesting an enhancing interacting role of H-ras and EpoR in erythroid proliferation/differentiation. Bone Marrow Transplantation (2000) 26, 817–822.

  • Human multipotential progenitor cells (CFU-GEMM) have extensive replating capacity for secondary CFU-GEMM: an effect enhanced by cord blood plasma
    Blood, 1993
    Co-Authors: C Carow, Giao Hangoc, He Broxmeyer
    Abstract:

    The replating capability of human umbilical cord blood (CB) multipotential (CFU-GEMM) progenitors was assessed in vitro as an estimate of self-renewal using erythropoietin (Epo), steel factor (SLF), and either fetal bovine serum (FBS) or CB plasma. This study found a much higher replating efficiency for CB CFU-GEMM than previously reported, in terms of the percentage of colonies that could be replated, the number of secondary colonies per replated primary colony, and the size of secondary colonies. Moreover, the majority of secondary colonies were CFU-GEMM-derived. Although the percentages of bone marrow CFU-GEMM that replate was similar to that for CB CFU-GEMM and the sizes of secondary bone marrow and CB CFU-GEMM were also similar, replated CB CFU-GEMM gave rise to far greater numbers of secondary colonies. No tertiary colonies were observed when secondary CFU-GEMM were replated. Detection of extensive secondary replating potential was enhanced by the addition of CB plasma to the cultures. This activity was not found in either adult blood (PB) plasma, umbilical cord vein endothelial cell-conditioned medium (ECCM), FBS plus ECCM, or FBS plus the combination of interleukin-1 (IL-1), IL-3, IL-6, IL-11, granulocyte colony-stimulating factor, and granulocyte- macrophage colony-stimulating factor. Whether the CB plasma-enhancing activity for CFU-GEMM replating capacity is attributable to a novel factor or factors, or represents effects of other known cytokines, alone or in combination, remains to be determined. Of particular relevance, these studies suggest that human CFU-GEMM have some degree of stemness and perhaps should be classified as a subset of stem cells.