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Expansion and preservation of the functional activity of adult hematopoietic stem cells cultured ex vivo with a histone deacetylase inhibitor.
- Source :
-
Stem cells translational medicine [Stem Cells Transl Med] 2020 Apr; Vol. 9 (4), pp. 531-542. Date of Electronic Publication: 2020 Jan 17. - Publication Year :
- 2020
-
Abstract
- Attempts to expand ex vivo the numbers of human hematopoietic stem cells (HSCs) without compromising their marrow repopulating capacity and their ability to establish multilineage hematopoiesis has been the subject of intense investigation. Although most such efforts have focused on cord blood HSCs, few have been applied to adult HSCs, a more clinically relevant HSC source for gene modification. To date, the strategies that have been used to expand adult HSCs have resulted in modest effects or HSCs with lineage bias and a limited ability to generate T cells in vivo. We previously reported that culturing umbilical cord blood CD34+ cells in serum-free media supplemented with valproic acid (VPA), a histone deacetylase inhibitor, and a combination of cytokines led to the expansion of the numbers of fully functional HSCs. In the present study, we used this same approach to expand the numbers of adult human CD34+ cells isolated from mobilized peripheral blood and bone marrow. This approach resulted in a significant increase in the numbers of phenotypically defined HSCs (CD34+CD45RA-CD90+D49f+). Cells incubated with VPA also exhibited increased aldehyde dehydrogenase activity and decreased mitochondrial membrane potential, each functional markers of HSCs. Grafts harvested from VPA-treated cultures were able to engraft in immune-deficient mice and, importantly, to generate cellular progeny belonging to each hematopoietic lineage in similar proportion to that observed with unmanipulated CD34+ cells. These data support the utility of VPA-mediated ex vivo HSC expansion for gene modification of adult HSCs.<br /> (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Subjects :
- Adult
Animals
Bone Marrow Cells cytology
Bone Marrow Cells drug effects
Cell Count
Cell Lineage drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Cells, Cultured
Cytokines metabolism
Female
Fetal Blood cytology
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells drug effects
Humans
Mice, Inbred NOD
Mice, SCID
Phenotype
Valproic Acid pharmacology
Adult Stem Cells cytology
Hematopoietic Stem Cells cytology
Histone Deacetylase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2157-6580
- Volume :
- 9
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Stem cells translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31950644
- Full Text :
- https://doi.org/10.1002/sctm.19-0199