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Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome

BACKGROUND: Efficient and sustained hematopoietic recovery after hematopoietic stem cell or bone marrow transplantation is supported by paracrine signaling from specific subpopulations of mesenchymal stromal cells (MSCs). Here, we considered whether in vitro mechanopriming of human MSCs could be adm...

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Autores principales: Liu, Frances D., Tam, Kimberley, Pishesha, Novalia, Poon, Zhiyong, Van Vliet, Krystyn J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199758/
https://www.ncbi.nlm.nih.gov/pubmed/30352620
http://dx.doi.org/10.1186/s13287-018-0982-2
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author Liu, Frances D.
Tam, Kimberley
Pishesha, Novalia
Poon, Zhiyong
Van Vliet, Krystyn J.
author_facet Liu, Frances D.
Tam, Kimberley
Pishesha, Novalia
Poon, Zhiyong
Van Vliet, Krystyn J.
author_sort Liu, Frances D.
collection PubMed
description BACKGROUND: Efficient and sustained hematopoietic recovery after hematopoietic stem cell or bone marrow transplantation is supported by paracrine signaling from specific subpopulations of mesenchymal stromal cells (MSCs). Here, we considered whether in vitro mechanopriming of human MSCs could be administered to predictively and significantly improve in vivo hematopoietic recovery after irradiation injury. METHODS: First, we implemented regression modeling to identify eight MSC-secreted proteins that correlated strongly with improved rescue from radiation damage, including hematopoietic recovery, in a murine model of hematopoietic failure. Using these partial least squares regression (PLSR) model parameters, we then predicted recovery potential of MSC populations that were culture expanded on substrata of varying mechanical stiffness. Lastly, we experimentally validated these predictions using an in vitro co-culture model of hematopoiesis and using new in vivo experiments for the same irradiation injury model used to generate survival predictions. RESULTS: MSCs grown on the least stiff (elastic moduli ~ 1 kPa) of these polydimethylsiloxane (PDMS) substrata secreted high concentrations of key proteins identified in regression modeling, at concentrations comparable to those secreted by minor subpopulations of MSCs shown previously to be effective in supporting such radiation rescue. We confirmed that these MSCs expanded on PDMS could promote hematopoiesis in an in vitro co-culture model with hematopoietic stem and progenitor cells (HSPCs). Further, MSCs cultured on PDMS of highest stiffness (elastic moduli ~ 100 kPa) promoted expression of CD123(+) HSPCs, indicative of myeloid differentiation. Systemic administration of mechanoprimed MSCs resulted in improved mouse survival and weight recovery after bone marrow ablation, as compared with both standard MSC expansion on stiffer materials and with biophysically sorted MSC subpopulations. Additionally, we observed recovery of white blood cells, platelets, and red blood cells, indicative of complete recovery of all hematopoietic lineages. CONCLUSIONS: These results demonstrate that computational techniques to identify MSC biomarkers can be leveraged to predict and engineer therapeutically effective MSC phenotypes defined by mechanoprimed secreted factors, for translational applications including hematopoietic recovery. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13287-018-0982-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-61997582018-10-31 Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome Liu, Frances D. Tam, Kimberley Pishesha, Novalia Poon, Zhiyong Van Vliet, Krystyn J. Stem Cell Res Ther Research BACKGROUND: Efficient and sustained hematopoietic recovery after hematopoietic stem cell or bone marrow transplantation is supported by paracrine signaling from specific subpopulations of mesenchymal stromal cells (MSCs). Here, we considered whether in vitro mechanopriming of human MSCs could be administered to predictively and significantly improve in vivo hematopoietic recovery after irradiation injury. METHODS: First, we implemented regression modeling to identify eight MSC-secreted proteins that correlated strongly with improved rescue from radiation damage, including hematopoietic recovery, in a murine model of hematopoietic failure. Using these partial least squares regression (PLSR) model parameters, we then predicted recovery potential of MSC populations that were culture expanded on substrata of varying mechanical stiffness. Lastly, we experimentally validated these predictions using an in vitro co-culture model of hematopoiesis and using new in vivo experiments for the same irradiation injury model used to generate survival predictions. RESULTS: MSCs grown on the least stiff (elastic moduli ~ 1 kPa) of these polydimethylsiloxane (PDMS) substrata secreted high concentrations of key proteins identified in regression modeling, at concentrations comparable to those secreted by minor subpopulations of MSCs shown previously to be effective in supporting such radiation rescue. We confirmed that these MSCs expanded on PDMS could promote hematopoiesis in an in vitro co-culture model with hematopoietic stem and progenitor cells (HSPCs). Further, MSCs cultured on PDMS of highest stiffness (elastic moduli ~ 100 kPa) promoted expression of CD123(+) HSPCs, indicative of myeloid differentiation. Systemic administration of mechanoprimed MSCs resulted in improved mouse survival and weight recovery after bone marrow ablation, as compared with both standard MSC expansion on stiffer materials and with biophysically sorted MSC subpopulations. Additionally, we observed recovery of white blood cells, platelets, and red blood cells, indicative of complete recovery of all hematopoietic lineages. CONCLUSIONS: These results demonstrate that computational techniques to identify MSC biomarkers can be leveraged to predict and engineer therapeutically effective MSC phenotypes defined by mechanoprimed secreted factors, for translational applications including hematopoietic recovery. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13287-018-0982-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-24 /pmc/articles/PMC6199758/ /pubmed/30352620 http://dx.doi.org/10.1186/s13287-018-0982-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Liu, Frances D.
Tam, Kimberley
Pishesha, Novalia
Poon, Zhiyong
Van Vliet, Krystyn J.
Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
title Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
title_full Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
title_fullStr Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
title_full_unstemmed Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
title_short Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
title_sort improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199758/
https://www.ncbi.nlm.nih.gov/pubmed/30352620
http://dx.doi.org/10.1186/s13287-018-0982-2
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