The human–sheep chimeras as a model for human stem cell mobilization and evaluation of hematopoietic grafts' potential

Almeida-Porada, Graça; Porada, Christopher D.; Gupta, Nicole; Torabi, Alireza; Thain, David; Zanjani, Esmail D.

doi:10.1016/j.exphem.2007.07.009

Cited by 40 publications

(26 citation statements)

References 41 publications

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“…These results are consistent with numerous previous reports that hematopoietic chimerism observed naturally in twin gestations (30) and following in utero transplantation in multiple animal models (3,5,14,31,32) and in humans (33) can lead to donor-specific tolerance. Thus, fetal tolerance induction for stem cell transplantation remains an important and approachable clinical goal.…”

Section: Discussionsupporting

confidence: 82%

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Nijagal¹,

Wegorzewska²,

Jarvis³

et al. 2011

J. Clin. Invest.

125

133

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Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell-deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.

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Section: Discussionsupporting

confidence: 82%

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Nijagal¹,

Wegorzewska²,

Jarvis³

et al. 2011

J. Clin. Invest.

125

133

View full text Add to dashboard Cite

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“…Some of the potential advantages of this model include its recapitulation of the physiological and developmental characteristics of the human fetus, making it a great model for intra-uterine hematopoietic cell transplantation (ref). and the capability for efficient and safe manipulation early in gestation [53]. Moreover, the relatively long life span and large size of these animals allows for the repeated and long term evaluation of donor cell activity and increased sensitivity for detection of engraftment [54].…”

Section: Discussionmentioning

confidence: 99%

Generation of CD34+ cells from human embryonic stem cells using a clinically applicable methodology and engraftment in the fetal sheep model

Kim¹,

Zanjani²,

Jeanblanc³

et al. 2013

Experimental Hematology

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Until now, ex vivo generation of CD34+ hematopoietic stem cells (HSCs) from human embryonic stem cells (hESCs) mostly involved use of feeder cells of non-human origin. While they provided invaluable models to study hematopoiesis, in vivo engraftment of hESC-derived HSCs remains a challenging task. In this study, we used a novel coculture system comprised of human bone marrow derived mesenchymal stromal/stem cells (MSCs) and peripheral blood CD14+ monocyte-derived macrophages to generate CD34+ cells from hESCs in vitro. Human ESC-derived CD34+ cells generated using this method expressed surface makers associated with adult human HSCs and up-regulated hematopoietic stem cell genes compared to human bone marrow-derived CD34+ cells. Finally, transplantation of purified hESC-derived CD34+ cells into the pre-immune fetal sheep, primed with transplantation of MSCs derived from the same hESC line, demonstrated multi-lineage hematopoietic activity with graft presence up to 16 weeks post-transplantation. This in vivo demonstration of engraftment and robust multi-lineage hematopoietic activity by hESC-derived CD34+ cells lends credence to the translational value and potential clinical utility of this novel differentiation and transplantation protocol.

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“…The engraftment frequency (chimeric index) was 79% with functional engraftment at 50% (62.5% of chimeric sheep). This was seen without manipulations designed to improve graft expression (10, 15). Serum C-peptide concentrations in some sheep approached basal levels seen in humans 1.86-4.49 ng/mL (46).…”

Section: Discussionmentioning

confidence: 99%

“…This model has proved useful in refining our knowledge of immune tolerance to self, transplantation tolerance, stem cell compartments, stem cell physiology and cell/tissue transplantation (11-15). The theoretical basis rests in the well-recognized propensity of the fetus for transplantation tolerance (16, 17).…”

Section: Introductionmentioning

confidence: 99%

Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells

Ersek

Pixley

Goodrich

et al. 2010

Experimental Hematology

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Objective-To determine if mesenchymal stem cells (MSC) derived from human fetal pancreatic tissue (pMSC) would engraft and differentiate in sheep pancreas following transplantation in utero.Methods-A three-step culture system was established for generating human fetal pMSC. Sheep fetuses were transplanted during the fetal transplant receptivity period with human pMSC and evaluated for in situ and functional engraftment in their pancreas, liver and bone marrow.Results-Isolation and expansion of adherent cells from the human fetal pancreas yielded a cell population with morphologic and phenotypic characteristics similar to MSC derived from bone marrow. This putative stem cell population could undergo multilineage differentiation in vitro. Three to 27 months after fetal transplantation, the pancreatic engraftment frequency (chimeric index) was 79% while functional engraftment was noted in 50% of transplanted sheep. Hepatic and marrow engraftment and expression was noted as well.Conclusion-We have established a procedure for isolation of human fetal pMSC that display characteristics similar to bone marrow derived MSC. In vivo results suggest the pMSC engraft, differentiate and secrete human insulin from the sheep pancreas.

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The human–sheep chimeras as a model for human stem cell mobilization and evaluation of hematopoietic grafts' potential

Cited by 40 publications

References 41 publications

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Generation of CD34+ cells from human embryonic stem cells using a clinically applicable methodology and engraftment in the fetal sheep model

Persistent circulating human insulin in sheep transplanted in utero with human mesenchymal stem cells

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