Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis

Abstract The only available option to treat radiation-induced hematopoietic syndrome is allogeneic hematopoietic cell transplantation, a therapy unavailable to many patients undergoing treatment for malignancy, which would also be infeasible in a radiological disaster. Stromal cells serve as critica...

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Autores principales:	Miguel F. Diaz, Pau lina D. Horton, Sandeep P. Dumbali, Akshita Kumar, Megan Livingston, Max A. Skibber, Amina Mohammadalipour, Brijesh S. Gill, Songlin Zhang, Charles S. Cox, Pamela L. Wenzel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fe396376d80247989e626bcbba03e9ec
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spelling	oai:doaj.org-article:fe396376d80247989e626bcbba03e9ec2021-12-02T12:42:17ZBone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis10.1038/s41598-020-79278-y2045-2322https://doaj.org/article/fe396376d80247989e626bcbba03e9ec2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79278-yhttps://doaj.org/toc/2045-2322Abstract The only available option to treat radiation-induced hematopoietic syndrome is allogeneic hematopoietic cell transplantation, a therapy unavailable to many patients undergoing treatment for malignancy, which would also be infeasible in a radiological disaster. Stromal cells serve as critical components of the hematopoietic stem cell niche and are thought to protect hematopoietic cells under stress. Prior studies that have transplanted mesenchymal stromal cells (MSCs) without co-administration of a hematopoietic graft have shown underwhelming rescue of endogenous hematopoiesis and have delivered the cells within 24 h of radiation exposure. Herein, we examine the efficacy of a human bone marrow-derived MSC therapy delivered at 3 h or 30 h in ameliorating radiation-induced hematopoietic syndrome and show that pancytopenia persists despite MSC therapy. Animals exposed to radiation had poorer survival and experienced loss of leukocytes, platelets, and red blood cells. Importantly, mice that received a therapeutic dose of MSCs were significantly less likely to die but experienced equivalent collapse of the hematopoietic system. The cause of the improved survival was unclear, as complete blood counts, splenic and marrow cellularity, numbers and function of hematopoietic stem and progenitor cells, and frequency of niche cells were not significantly improved by MSC therapy. Moreover, human MSCs were not detected in the bone marrow. MSC therapy reduced crypt dropout in the small intestine and promoted elevated expression of growth factors with established roles in gut development and regeneration, including PDGF-A, IGFBP-3, IGFBP-2, and IGF-1. We conclude that MSC therapy improves survival not through overt hematopoietic rescue but by positive impact on other radiosensitive tissues, such as the intestinal mucosa. Collectively, these data reveal that MSCs could be an effective countermeasure in cancer patients and victims of nuclear accidents but that MSCs alone do not significantly accelerate or contribute to recovery of the blood system.Miguel F. DiazPau lina D. HortonSandeep P. DumbaliAkshita KumarMegan LivingstonMax A. SkibberAmina MohammadalipourBrijesh S. GillSonglin ZhangCharles S. CoxPamela L. WenzelNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-19 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Miguel F. Diaz Pau lina D. Horton Sandeep P. Dumbali Akshita Kumar Megan Livingston Max A. Skibber Amina Mohammadalipour Brijesh S. Gill Songlin Zhang Charles S. Cox Pamela L. Wenzel Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
description	Abstract The only available option to treat radiation-induced hematopoietic syndrome is allogeneic hematopoietic cell transplantation, a therapy unavailable to many patients undergoing treatment for malignancy, which would also be infeasible in a radiological disaster. Stromal cells serve as critical components of the hematopoietic stem cell niche and are thought to protect hematopoietic cells under stress. Prior studies that have transplanted mesenchymal stromal cells (MSCs) without co-administration of a hematopoietic graft have shown underwhelming rescue of endogenous hematopoiesis and have delivered the cells within 24 h of radiation exposure. Herein, we examine the efficacy of a human bone marrow-derived MSC therapy delivered at 3 h or 30 h in ameliorating radiation-induced hematopoietic syndrome and show that pancytopenia persists despite MSC therapy. Animals exposed to radiation had poorer survival and experienced loss of leukocytes, platelets, and red blood cells. Importantly, mice that received a therapeutic dose of MSCs were significantly less likely to die but experienced equivalent collapse of the hematopoietic system. The cause of the improved survival was unclear, as complete blood counts, splenic and marrow cellularity, numbers and function of hematopoietic stem and progenitor cells, and frequency of niche cells were not significantly improved by MSC therapy. Moreover, human MSCs were not detected in the bone marrow. MSC therapy reduced crypt dropout in the small intestine and promoted elevated expression of growth factors with established roles in gut development and regeneration, including PDGF-A, IGFBP-3, IGFBP-2, and IGF-1. We conclude that MSC therapy improves survival not through overt hematopoietic rescue but by positive impact on other radiosensitive tissues, such as the intestinal mucosa. Collectively, these data reveal that MSCs could be an effective countermeasure in cancer patients and victims of nuclear accidents but that MSCs alone do not significantly accelerate or contribute to recovery of the blood system.
format	article
author	Miguel F. Diaz Pau lina D. Horton Sandeep P. Dumbali Akshita Kumar Megan Livingston Max A. Skibber Amina Mohammadalipour Brijesh S. Gill Songlin Zhang Charles S. Cox Pamela L. Wenzel
author_facet	Miguel F. Diaz Pau lina D. Horton Sandeep P. Dumbali Akshita Kumar Megan Livingston Max A. Skibber Amina Mohammadalipour Brijesh S. Gill Songlin Zhang Charles S. Cox Pamela L. Wenzel
author_sort	Miguel F. Diaz
title	Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
title_short	Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
title_full	Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
title_fullStr	Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
title_full_unstemmed	Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
title_sort	bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/fe396376d80247989e626bcbba03e9ec
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Bone marrow stromal cell therapy improves survival after radiation injury but does not restore endogenous hematopoiesis

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