Editors' ChoiceStem Cells

Niche guidance of hematopoietic differentiation

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Science Translational Medicine  01 Apr 2015:
Vol. 7, Issue 281, pp. 281ec54
DOI: 10.1126/scitranslmed.aab0841

Although pluripotent stem cells have the potential to give rise to the numerous diverse cell types within the body, obtaining lineage-restricted progenitors at high efficiency remains the rate-limiting step for generation of cells for transplantation. The production of hematopoietic progenitor cells and their lineages has remained especially challenging. Now, Gori et al. demonstrate that hematopoietic progenitor cells can be efficiently generated by integrating key components of the vascular niche.

Stem cell niches are key anatomic locations that provide instructive signaling to control the balance between self-renewal and differentiation. The concept of the niche has also served as the inspiration for key components necessary for lineage-specific differentiation of pluripotent stem cells for clinical use. The authors used pluripotent and induced pluripotent stem cells from human and nonhuman primate sources to demonstrate that hematopoietic progenitor cells can be generated using components of the Notch signaling axis that are present in the hematopoietic niche. The co-culture of pluripotent stem cells with endothelial cells, which produce key Notch ligands Jagged 1 and Delta-like 4, increased hematopoietic progenitor cell yield and engraftment into xenograft models. Integrating key cytokines, such as prostaglandin E2, into the co-culture with endothelial cells further increased hematopoietic progenitor cell yield and engraftment. By genetically modifying the cells to be resistant to chemotherapy, the authors then demonstrated that engraftment could be increased fourfold in vivo in combination with chemotherapy. Finally, the authors showed that the differentiation of hematopoietic progenitor cells into myeloid and lymphoid lineages in secondary transplants was maintained by endothelial cell co-culture and not by cytokines alone.

The hematopoietic system has been the prototypic system for the study of stem cells in vivo, but the generation of lineage-specific populations in vitro has remained challenging. Follow-up studies validating the effectiveness of this method of hematopoietic progenitor cell generation and transplantation in the context of disease models will help expand the potential of cell therapy for patients with hematologic disorders.

J. L. Gori et al., Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells. J. Clin. Invest. 125,1243–1254 (2015). [Full Text]

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