Mesenchymal stromal cells improve the transplantation outcome of CRISPR-Cas9 gene-edited human HSPCs.
DNA-damage response
genome editing
hematopoietic stem and progenitor cells
hematopoietic support
mesenchymal stromal cells
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
04 01 2023
04 01 2023
Historique:
received:
25
02
2022
revised:
29
07
2022
accepted:
12
08
2022
pmc-release:
04
01
2024
pubmed:
20
8
2022
medline:
10
1
2023
entrez:
19
8
2022
Statut:
ppublish
Résumé
Mesenchymal stromal cells (MSCs) have been employed in vitro to support hematopoietic stem and progenitor cell (HSPC) expansion and in vivo to promote HSPC engraftment. Based on these studies, we developed an MSC-based co-culture system to optimize the transplantation outcome of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene-edited (GE) human HSPCs. We show that bone marrow (BM)-MSCs produce several hematopoietic supportive and anti-inflammatory factors capable of alleviating the proliferation arrest and mitigating the apoptotic and inflammatory programs activated in GE-HSPCs, improving their expansion and clonogenic potential in vitro. The use of BM-MSCs resulted in superior human engraftment and increased clonal output of GE-HSPCs contributing to the early phase of hematological reconstitution in the peripheral blood of transplanted mice. In conclusion, our work poses the biological bases for a novel clinical use of BM-MSCs to promote engraftment of GE-HSPCs and improve their transplantation outcome.
Identifiants
pubmed: 35982622
pii: S1525-0016(22)00499-3
doi: 10.1016/j.ymthe.2022.08.011
pmc: PMC9840125
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
230-248Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests L.N., P.G., and S.F. are inventors of patents on applications of GE in HSPCs owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation. L.N. is the founder and a quota holder and P.G. is a quota holder of GeneSpire, a startup company aiming to develop ex vivo GE in genetic diseases. The remaining authors have no conflicts of interest to declare.
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