Cargando…
Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells
Ex vivo expansion strategies of human hematopoietic stem cell (HSC) grafts with suboptimal stem cell dose have emerged as promising strategies for improving outcomes of HSC transplantation in patients with hematological malignancies. While exposure of HSCs to ex vivo cultures expands the number of p...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769876/ https://www.ncbi.nlm.nih.gov/pubmed/33384995 http://dx.doi.org/10.3389/fcell.2020.592348 |
_version_ | 1783629420814139392 |
---|---|
author | Papa, Luena Djedaini, Mansour Martin, Tiphaine C. Zangui, Mahtab Beaumont, Kristin G. Sebra, Robert Parsons, Ramon Schaniel, Christoph Hoffman, Ronald |
author_facet | Papa, Luena Djedaini, Mansour Martin, Tiphaine C. Zangui, Mahtab Beaumont, Kristin G. Sebra, Robert Parsons, Ramon Schaniel, Christoph Hoffman, Ronald |
author_sort | Papa, Luena |
collection | PubMed |
description | Ex vivo expansion strategies of human hematopoietic stem cell (HSC) grafts with suboptimal stem cell dose have emerged as promising strategies for improving outcomes of HSC transplantation in patients with hematological malignancies. While exposure of HSCs to ex vivo cultures expands the number of phenotypically identifiable HSCs, it frequently alters the transcriptomic and metabolic profiles, therefore, compromising their long-term (LT) hematopoietic reconstitution capacity. Within the heterogeneous pool of expanded HSCs, the precise phenotypic, transcriptomic and metabolic profile and thus, the identity of HSCs that confer LT repopulation potential remains poorly described. Utilizing valproic acid (VPA) in ex vivo cultures of umbilical cord blood (UCB)-CD34(+) cells, we demonstrate that expanded HSCs phenotypically marked by expression of the stem cell markers CD34, CD90 and EPCR (CD201) are highly enriched for LT-HSCs. Furthermore, we report that low mitochondrial membrane potential, and, hence, mitochondrial activity distinguishes LT-HSCs within the expanded pool of phenotypically defined HSCs. Remarkably, such reduced mitochondrial activity is restricted to cells with the highest expression levels of CD34, CD90 and EPCR phenotypic markers. Together, our findings reveal that high expression of CD34, CD90 and EPCR in conjunction with low mitochondrial activity is critical for identification of functional LT-HSCs generated within ex vivo expansion cultures. |
format | Online Article Text |
id | pubmed-7769876 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77698762020-12-30 Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells Papa, Luena Djedaini, Mansour Martin, Tiphaine C. Zangui, Mahtab Beaumont, Kristin G. Sebra, Robert Parsons, Ramon Schaniel, Christoph Hoffman, Ronald Front Cell Dev Biol Cell and Developmental Biology Ex vivo expansion strategies of human hematopoietic stem cell (HSC) grafts with suboptimal stem cell dose have emerged as promising strategies for improving outcomes of HSC transplantation in patients with hematological malignancies. While exposure of HSCs to ex vivo cultures expands the number of phenotypically identifiable HSCs, it frequently alters the transcriptomic and metabolic profiles, therefore, compromising their long-term (LT) hematopoietic reconstitution capacity. Within the heterogeneous pool of expanded HSCs, the precise phenotypic, transcriptomic and metabolic profile and thus, the identity of HSCs that confer LT repopulation potential remains poorly described. Utilizing valproic acid (VPA) in ex vivo cultures of umbilical cord blood (UCB)-CD34(+) cells, we demonstrate that expanded HSCs phenotypically marked by expression of the stem cell markers CD34, CD90 and EPCR (CD201) are highly enriched for LT-HSCs. Furthermore, we report that low mitochondrial membrane potential, and, hence, mitochondrial activity distinguishes LT-HSCs within the expanded pool of phenotypically defined HSCs. Remarkably, such reduced mitochondrial activity is restricted to cells with the highest expression levels of CD34, CD90 and EPCR phenotypic markers. Together, our findings reveal that high expression of CD34, CD90 and EPCR in conjunction with low mitochondrial activity is critical for identification of functional LT-HSCs generated within ex vivo expansion cultures. Frontiers Media S.A. 2020-12-15 /pmc/articles/PMC7769876/ /pubmed/33384995 http://dx.doi.org/10.3389/fcell.2020.592348 Text en Copyright © 2020 Papa, Djedaini, Martin, Zangui, Beaumont, Sebra, Parsons, Schaniel and Hoffman. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Papa, Luena Djedaini, Mansour Martin, Tiphaine C. Zangui, Mahtab Beaumont, Kristin G. Sebra, Robert Parsons, Ramon Schaniel, Christoph Hoffman, Ronald Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells |
title | Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells |
title_full | Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells |
title_fullStr | Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells |
title_full_unstemmed | Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells |
title_short | Limited Mitochondrial Activity Coupled With Strong Expression of CD34, CD90 and EPCR Determines the Functional Fitness of ex vivo Expanded Human Hematopoietic Stem Cells |
title_sort | limited mitochondrial activity coupled with strong expression of cd34, cd90 and epcr determines the functional fitness of ex vivo expanded human hematopoietic stem cells |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769876/ https://www.ncbi.nlm.nih.gov/pubmed/33384995 http://dx.doi.org/10.3389/fcell.2020.592348 |
work_keys_str_mv | AT papaluena limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT djedainimansour limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT martintiphainec limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT zanguimahtab limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT beaumontkristing limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT sebrarobert limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT parsonsramon limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT schanielchristoph limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells AT hoffmanronald limitedmitochondrialactivitycoupledwithstrongexpressionofcd34cd90andepcrdeterminesthefunctionalfitnessofexvivoexpandedhumanhematopoieticstemcells |