title: Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls.
abstract: Critical limb ischemia (CLI) is often poorly treatable by conventional management and alternatives such as autologous cell therapy are increasingly investigated. Whereas previous studies showed a substantial impairment of neovascularization capacity in primary bone-marrow (BM) isolates from patients, little is known about dysfunction in patient-derived BM mesenchymal stromal cells (MSCs). In this study, we have compared CLI-MSCs to healthy controls using gene expression profiling and functional assays for differentiation, senescence and in vitro and in vivo pro-angiogenic ability. Whereas no differentially expressed genes were found and adipogenic and osteogenic differentiation did not significantly differ between groups, chondrogenic differentiation was impaired in CLI-MSCs, potentially as a consequence of increased senescence. Migration experiments showed no differences in growth factor sensitivity and secretion between CLI- and control MSCs. In a murine hind-limb ischemia model, recovery of perfusion was enhanced in MSC-treated mice compared to vehicle controls (71 ± 24% versus 44 ± 11%; P < 1 × 10(-6)). CLI-MSC- and control-MSC-treated animals showed nearly identical amounts of reperfusion (ratio CLI:Control = 0.98, 95% CI = 0.82-1.14), meeting our criteria for statistical equivalence. The neovascularization capacity of MSCs derived from CLI-patients is not compromised and equivalent to that of control MSCs, suggesting that autologous MSCs are suitable for cell therapy in CLI patients.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Gremmels
authors.affiliation: 1] Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands [2] Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Teraa
authors.affiliation: 1] Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands [2] Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Paul Ha
authors.initials: PH
authors.lastname: Quax
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Krista
authors.initials: K
authors.lastname: den Ouden
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Joost O
authors.initials: JO
authors.lastname: Fledderus
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D016922:Cellular Senescence; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D064368:Healthy Volunteers; D006801:Humans; D007511:Ischemia / Q000473:pathology* / Q000628:therapy*; D007866:Leg / Q000098:blood supply / Q000473:pathology*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D018919:Neovascularization, Physiologic