PMID- 28295901 OWN - NLM STAT- MEDLINE DCOM- 20180223 LR - 20181202 IS - 1549-4918 (Electronic) IS - 1066-5099 (Linking) VI - 35 IP - 6 DP - 2017 Jun TI - High Aldehyde Dehydrogenase Activity Identifies a Subset of Human Mesenchymal Stromal Cells with Vascular Regenerative Potential. PG - 1542-1553 LID - 10.1002/stem.2612 [doi] AB - During culture expansion, multipotent mesenchymal stromal cells (MSCs) differentially express aldehyde dehydrogenase (ALDH), an intracellular detoxification enzyme that protects long-lived cells against oxidative stress. Thus, MSC selection based on ALDH-activity may be used to reduce heterogeneity and distinguish MSC subsets with improved regenerative potency. After expansion of human bone marrow-derived MSCs, cell progeny was purified based on low versus high ALDH-activity (ALDH(hi) ) by fluorescence-activated cell sorting, and each subset was compared for multipotent stromal and provascular regenerative functions. Both ALDH(l) degrees and ALDH(hi) MSC subsets demonstrated similar expression of stromal cell (>95% CD73(+) , CD90(+) , CD105(+) ) and pericyte (>95% CD146(+) ) surface markers and showed multipotent differentiation into bone, cartilage, and adipose cells in vitro. Conditioned media (CDM) generated by ALDH(hi) MSCs demonstrated a potent proliferative and prosurvival effect on human microvascular endothelial cells (HMVECs) under serum-free conditions and augmented HMVEC tube-forming capacity in growth factor-reduced matrices. After subcutaneous transplantation within directed in vivo angiogenesis assay implants into immunodeficient mice, ALDH(hi) MSC or CDM produced by ALDH(hi) MSC significantly augmented murine vascular cell recruitment and perfused vessel infiltration compared with ALDH(l) degrees MSC. Although both subsets demonstrated strikingly similar mRNA expression patterns, quantitative proteomic analyses performed on subset-specific CDM revealed the ALDH(hi) MSC subset uniquely secreted multiple proangiogenic cytokines (vascular endothelial growth factor beta, platelet derived growth factor alpha, and angiogenin) and actively produced multiple factors with chemoattractant (transforming growth factor-beta, C-X-C motif chemokine ligand 1, 2, and 3 (GRO), C-C motif chemokine ligand 5 (RANTES), monocyte chemotactic protein 1 (MCP-1), interleukin [IL]-6, IL-8) and matrix-modifying functions (tissue inhibitor of metalloprotinase 1 & 2 (TIMP1/2)). Collectively, MSCs selected for ALDH(hi) demonstrated enhanced proangiogenic secretory functions and represent a purified MSC subset amenable for vascular regenerative applications. Stem Cells 2017;35:1542-1553. CI - (c) 2017 AlphaMed Press. FAU - Sherman, Stephen E AU - Sherman SE AD - Krembil Centre for Stem Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, London, Ontario, Canada. AD - Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. FAU - Kuljanin, Miljan AU - Kuljanin M AD - Don Rix Protein Identification Facility, Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. FAU - Cooper, Tyler T AU - Cooper TT AD - Krembil Centre for Stem Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, London, Ontario, Canada. AD - Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. FAU - Putman, David M AU - Putman DM AD - Krembil Centre for Stem Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, London, Ontario, Canada. AD - Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. FAU - Lajoie, Gilles A AU - Lajoie GA AD - Don Rix Protein Identification Facility, Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. FAU - Hess, David A AU - Hess DA AUID- ORCID: 0000-0003-2186-3166 AD - Krembil Centre for Stem Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, London, Ontario, Canada. AD - Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. LA - eng PT - Journal Article DEP - 20170403 PL - England TA - Stem Cells JT - Stem cells (Dayton, Ohio) JID - 9304532 RN - 0 (Biomarkers) RN - 0 (Culture Media, Conditioned) RN - 0 (Proteome) RN - 0 (RNA, Messenger) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase) SB - IM MH - Aldehyde Dehydrogenase/*metabolism MH - Biomarkers/metabolism MH - Blood Vessel Prosthesis MH - Blood Vessels/drug effects/*physiology MH - Cell Differentiation/drug effects MH - Cell Proliferation/drug effects MH - Coculture Techniques MH - Culture Media, Conditioned/pharmacology MH - Endothelial Cells/cytology/drug effects MH - Humans MH - Mesenchymal Stem Cells/*cytology/drug effects/*enzymology MH - Microvessels/cytology MH - Multipotent Stem Cells/cytology/drug effects MH - Neovascularization, Physiologic/drug effects MH - Pericytes/cytology/drug effects MH - Proteome/metabolism MH - RNA, Messenger/genetics/metabolism MH - *Regeneration/drug effects MH - Stromal Cells/cytology/drug effects OTO - NOTNLM OT - Aldehyde dehydrogenase OT - Angiogenesis OT - Multipotent stromal cells OT - Peripheral artery disease OT - Proteomics OT - Transplantation EDAT- 2017/03/16 06:00 MHDA- 2018/02/24 06:00 CRDT- 2017/03/16 06:00 PHST- 2016/11/14 00:00 [received] PHST- 2017/01/20 00:00 [revised] PHST- 2017/02/19 00:00 [accepted] PHST- 2017/03/16 06:00 [pubmed] PHST- 2018/02/24 06:00 [medline] PHST- 2017/03/16 06:00 [entrez] AID - 10.1002/stem.2612 [doi] PST - ppublish SO - Stem Cells. 2017 Jun;35(6):1542-1553. doi: 10.1002/stem.2612. Epub 2017 Apr 3.