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 November 1, 2017; First 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 Stem cells Transplantation

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 6

Young EC coinfusion radioprotects the BM microenvironment.

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Young EC coinfusion radioprotects the BM microenvironment. Lethally irra...
Lethally irradiated (9.50 Gy) mice were coinfused with either 105 young or aged WBM cells and 5 × 105 young BM ECs. (A) Representative H&E-stained longitudinal femur sections from coinfused mice 7 days after irradiation (n = 10 mice/cohort). Original magnification, ×100. (B) Representative images of damaged VEGFR3+ femoral vessels, including type I hemorrhagic (asterisk), type I discontinuous (red arrow), and type II regressed (blue arrow), 7 days after irradiation, demonstrating radioprotection of the vascular niche (n = 10 mice/cohort). Sections were counterstained with hematoxylin. Original magnification, ×200. (C and D) Quantification of total BM CD45+ cells showing mitigation of panhematopoietic injury in cohorts coinfused with young or aged WBM and young ECs (n = 10 mice/cohort; data are related to A). (E and F) Quantification of type I/II damaged VEGFR3+ sinusoidal vessels in cohorts coinfused with young or aged WBM and young ECs (n = 10 mice/cohort; data are related to B). Error bars represent the sample mean ± SEM. ***P < 0.001, by unpaired, 2-tailed Student’s t test. Steady-state controls were used as a reference point and were not included in the statistical analysis.