Endothelial transplantation rejuvenates aged hematopoietic stem cell function
Michael G. Poulos, … , Sina Y. Rabbany, Jason M. Butler
Michael G. Poulos, … , Sina Y. Rabbany, Jason M. Butler
Published October 16, 2017
Citation Information: J Clin Invest. 2017;127(11):4163-4178. https://doi.org/10.1172/JCI93940.
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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 5

Coinfusion of young endothelium enhances BM transplantation.

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Coinfusion of young endothelium enhances BM transplantation. (A and B) S...
(A and B) Survival curves for mice transplanted with 105 WBM cells from either (A) young or (B) aged animals, showing an increase in overall survival in WBM cohorts coinfused with ECs (n = 10 mice/cohort). Note: Data in A and B share the same steady-state, PBS, and EC-alone controls. The survival curve significance between the WBM and WBM-plus-EC cohorts was calculated using a log-rank test. (C and D) Time course of hematopoietic recovery in the PB of recipient mice coinfused with 105 young or aged WBM cells, with or without young ECs. EC-coinfused animals had a significant increase in hematopoietic recovery (n = 10 mice/cohort). (E and F) Quantification of CFU-S in mice transplanted with 105 WBM cells from (E) young or (F) aged donors, with or without young ECs, demonstrating an increase in hematopoietic progenitor activity in cohorts coinfused with ECs. CFU-S numbers were scored 8 days after irradiation (n ≥ 5 mice/cohort). (G and H) Log-fraction plot of limiting dilution analysis showing the frequency of long-term multilineage repopulation of WBM from (G) young or (H) aged mice transplanted into lethally irradiated recipients and coinfused or not with young ECs (n = 10 mice/cohort). Dashed lines indicate 95% CIs. Stem cell frequency and significance were determined using ELDA. 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. Steady-state, PBS, and EC-alone controls were reference points and were not included in the statistical analysis.