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Vascular endothelial cells take hematopoietic stem cells to school

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Science Translational Medicine  15 Nov 2017:
Vol. 9, Issue 416, eaaq1236
DOI: 10.1126/scitranslmed.aaq1236

Abstract

The bone marrow vascular endothelial cell niche plays a critical role in regulating hematopoietic system aging by influencing the phenotype of hematopoietic stem cells

Aging is associated with changes in the hematopoietic system, including cell-intrinsic alterations of hematopoietic stem cells (HSCs), leading to a decline in HSC self-renewal, immune system dysregulation, and predisposition to myeloid neoplasms. The bone marrow (BM) microenvironment, consisting of the vascular endothelial cell (EC) and perivascular stromal niches, normally provides paracrine signals to support HSC maintenance and function. The function of the aging BM microenvironment—in particular, that of ECs—in the hematopoietic aging process is not well understood.

Poulos and colleagues used murine ex vivo hematopoietic stem and progenitor cell (HSPC)/EC coculture and in vivo EC infusion models to study the impact of ECs on hematopoietic system aging. Compared with young mice, the BM microenvironment of aged mice was characterized by increased vascular leakiness, metabolic dysregulation, and fewer ECs with impaired instructive function and decreased angiogenic potential. Furthermore, coculture of young HSPCs with aged ECs led to a significant decrease in HSC function and increased myeloid bias, whereas aged HSPCs cocultured with young ECs partially reversed the aging HSC phenotype. When young mice were exposed to myelosuppressive total body irradiation (TBI), infusion of young ECs promoted rapid hematopoietic recovery, whereas infusion of aged ECs promoted an aged phenotype including impaired HSC function and myeloid bias. Moreover, when aged mice exposed to TBI were infused with young ECs, there was a marked improvement in HSC function and hematologic recovery. Similarly, using a lethal irradiation and transplant model, co-infusion of young ECs with whole BM (WBM) cells from young or old donors improved HSC-repopulating activity, engraftment, and survival in recipient mice compared with infusions of donor WBM cells alone. These effects were, in part, related to mitigation of radiation-mediated damage to BM vascular microenvironment by the co-infused young ECs.

These results demonstrate that the BM vascular EC niche plays a key role in regulating hematopoietic system aging and that the HSC aging phenotype is characterized by impaired instructive functions of ECs. Although additional studies are required to further characterize the pathways and signals contributing to the EC-mediated HSC aging phenotype, the results suggest that cellular therapy with young ECs is a potentially promising strategy to revive aged HSC pools and accelerate hematopoietic recovery following myelosuppressive treatment regimens in elderly patients.

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