Endothelial transplantation rejuvenates aged hematopoietic stem cell function
Michael G. Poulos, Pradeep Ramalingam, Michael C. Gutkin, Pierre Llanos, Katherine Gilleran, Sina Y. Rabbany, Jason M. Butler
Michael G. Poulos, Pradeep Ramalingam, Michael C. Gutkin, Pierre Llanos, Katherine Gilleran, Sina Y. Rabbany, Jason M. Butler
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Concise Communication

Endothelial transplantation rejuvenates aged hematopoietic stem cell function

Abstract

Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs. We used an ex vivo hematopoietic stem and progenitor cell/EC (HSPC/EC) coculture system as well as in vivo EC infusions following myelosuppressive injury in mice to demonstrate that aged ECs impair the repopulating activity of young HSCs and impart a myeloid bias. Conversely, young ECs restored the repopulating capacity of aged HSCs but were unable to reverse the intrinsic myeloid bias. Infusion of young, HSC-supportive BM ECs enhanced hematopoietic recovery following myelosuppressive injury and restored endogenous HSC function in aged mice. Coinfusion of young ECs augmented aged HSC engraftment and enhanced overall survival in lethally irradiated mice by mitigating damage to the BM vascular microenvironment. These data lay the groundwork for the exploration of EC therapies that can serve as adjuvant modalities to enhance HSC engraftment and accelerate hematopoietic recovery in the elderly population following myelosuppressive regimens.

Authors

Michael G. Poulos, Pradeep Ramalingam, Michael C. Gutkin, Pierre Llanos, Katherine Gilleran, Sina Y. Rabbany, Jason M. Butler

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Figure 4

Infusion of young endothelium promotes hematopoietic recovery in aged recipients following myelosuppressive injury.

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Infusion of young endothelium promotes hematopoietic recovery in aged re...
(A) Schematic of the EC infusion strategy. (B and C) Time course of PB recovery of (B) young and (C) aged mice following irradiation (6.50 Gy) and infusion of either young ECs, aged ECs, or PBS vehicle control (n = 5 mice/cohort). The results demonstrated the myeloprotective effect of young EC transplantation following hematopoietic insult in both young and aged recipients, while the result with aged EC transplantation was indistinguishable from that observed in the PBS vehicle-infused controls. (D–F) Quantification of CD45.2+ donor chimerism and multilineage engraftment in PB 4 months after donor WBM transplantation as measured by flow cytometry (n = 5 mice/cohort). (D) Unmanipulated steady-state young and aged WBM was competitively transplanted to confirm reduced CD45.2+ hematopoietic engraftment and phenotypic CD11B+/GR1+ myeloid bias in the aged WBM transplantation cohort (n = 5 mice/cohort). (E) Young and (F) aged donors infused with young ECs demonstrated an increase in hematopoietic engraftment, while supporting an increase in B220+ and CD3+ lymphoid reconstitution. Error bars represent the sample mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed, Student’s t test for comparisons at individual time points. Steady-state and PBS controls were included as recovery reference points and were not included in the statistical analysis.