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Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.

ABSTRACT: We evaluated the healing potential of human fetal aorta-derived CD133(+) progenitor cells and their conditioned medium (CD133(+) CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2x10(4) CD133(+) or CD133(-) cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133(+) cells expressed high levels of wingless (Wnt) genes, which were downregulated following differentiation into CD133(-) cells along with upregulation of Wnt antagonists secreted frizzled-related protein (sFRP)-1, -3, and -4. CD133(+) cells accelerated wound closure as compared with CD133(-) or vehicle and promoted angiogenesis through stimulation of endothelial cell proliferation, migration, and survival by paracrine effects. CD133(+) cells secreted high levels of vascular endothelial growth factor (VEGF)-A and interleukin (IL)-8. Consistently, CD133(+) CCM accelerated wound closure and reparative angiogenesis, with this action abrogated by co-administering the Wnt antagonist sFRP-1 or neutralizing antibodies against VEGF-A or IL-8. In vitro, these effects were recapitulated following exposure of high-glucose-primed human umbilical vein endothelial cells to CD133(+) CCM, resulting in stimulation of migration, angiogenesis-like network formation and induction of Wnt expression. The promigratory and proangiogenic effect of CD133(+) CCM was blunted by sFRP-1, as well as antibodies against VEGF-A or IL-8. CD133(+) cells stimulate wound healing by paracrine mechanisms that activate Wnt signaling pathway in recipients. These preclinical findings open new perspectives for the cure of diabetic ulcers.

SUBMITTER: Barcelos LS

PROVIDER: S-EPMC2821014 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.

Barcelos Lucíola S LS Duplaa Cécile C Kränkel Nicolle N Graiani Gallia G Invernici Gloria G Katare Rajesh R Siragusa Mauro M Meloni Marco M Campesi Ilaria I Monica Manuela M Simm Andreas A Campagnolo Paola P Mangialardi Giuseppe G Stevanato Lara L Alessandri Giulio G Emanueli Costanza C Madeddu Paolo P

Circulation research 20090402 9

We evaluated the healing potential of human fetal aorta-derived CD133(+) progenitor cells and their conditioned medium (CD133(+) CCM) in a new model of ischemic diabetic ulcer. Streptozotocin-induced diabetic mice underwent bilateral limb ischemia and wounding. One wound was covered with collagen containing 2x10(4) CD133(+) or CD133(-) cells or vehicle. The contralateral wound, covered with only collagen, served as control. Fetal CD133(+) cells expressed high levels of wingless (Wnt) genes, whic ...[more]

PMID: 19342601

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Project description:BackgroundWhile rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers.MethodsThe angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial.ResultsHypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed.ConclusionsThe present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy.Trial registrationClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784.

Project description:BackgroundDiabetic foot ulcer (DFU) represents a highly-prevalent complication of diabetes mellitus (DM). Herein, the current study sought to identify the role of growth differentiation factor 10 (GDF-10) in wound healing in DFU via regulation of the transforming growth factor-beta 1 (TGF-β1)/Smad3 pathway.MethodsDM- and DFU-related microarray datasets GSE29221 and GSE134431 were firstly retrieved, and weighted gene co-expression network analysis (WGCNA) was carried out to construct a co-expression network affecting wound healing in DFU, followed by differential analysis. A protein-protein interaction (PPI) network of the DFU-related genes was subsequently constructed, and the core genes and signaling pathways in DFU were screened with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analyses. A DFU rat model was constructed for mechanism verification of the effect of GDF-10 on wound healing in DFU.ResultsWGCNA screened five co-expression modules, and the brown module was most closely-related to DM. Clustering analysis screened 4417 candidate genes, of which 175 differential genes were associated with wound healing, further involved in TGF-β1/Smad3 signaling pathway regulation of wound healing in DFU. The PPI network analysis predicted that GDF-10 might regulate the TGF-β1/Smad3 signaling pathway to participate in DFU development. Results of animal experimentation showed that the wound healing rates of NFU, DFU, DFU + GDF and GDF + SIS3 groups on the 22nd day were (87.66 ± 6.80)%, (56.31 ± 7.29)%, (71.64 ± 9.43)% and (55.09 ± 7.13)%, respectively. Besides, the expression of TGF-β1 in NFU, DFU, DFU + GDF and GDF + SIS3 groups was 0.988 ± 0.086, 0.297 ± 0.036, 0.447 ± 0.044, and 0.240 ± 0.050, respectively, and that of Smad3 was 1.009 ± 0.137, 0.145 ± 0.017, 0.368 ± 0.048, and 0.200 ± 0.028, respectively. Specifically, GDF-10 exerted a significant diminishing effect on fasting blood glucose level, and promoted wound healing in DFU rats, in addition to up-regulation of VEGF, FGF, Ang-1, TGF-β1, Smad3 and enhancement of IL-1b, IL-6, TNF-a and MMP-9, thereby promoting fibroblast proliferation, collagen deposition and angiogenesis.ConclusionsOur findings highlight that GDF-10 may promote angiogenesis by activating TGF-β1/Smad3 signaling, thereby promoting wound healing in DFU rats.

Project description:INTRODUCTION:One in four diabetes patients will develop a foot ulcer over their lifetime. The role of glycaemic control in the healing of foot ulcers in diabetes patients is not supported by randomised controlled trial (RCT) data. OBJECTIVES:To determine the feasibility of an RCT of glycaemic control with intensive insulin therapy in diabetic foot ulcer, by assessing: entry criteria, fasting capillary blood glucose (FCBG) medication satisfaction and sensitivity of different ulcer-healing endpoints to glycaemic control. DESIGN:Two substudies: one cross-sectional and one single-arm prospective. SETTING:Single-centre secondary care diabetic foot clinic in New Zealand. PARTICIPANTS:Substudy 1: 78 participants consisting of all people ?18 years with a diabetic foot ulcer presenting to the clinic over 35 weeks in 2015.Substudy 2: 15 participants from Substudy 1 consenting to intensive insulin therapy. INTERVENTION:Substudy 1: None.Substudy 2: Intensive insulin therapy with standard podiatry care over 24 weeks. OUTCOME:Substudy 1: Proportion of participants satisfying potential RCT entry criteria; medication satisfaction (Diabetes Medication Satisfaction).Substudy 2: FCBG, index ulcer healing time, index ulcer size, health-related quality of life (HRQoL; EuroQol 5 Dimensions 5 Levels and Diabetic Foot Ulcer Scale-Short Form). RESULTS:Proportion in Substudy 1 satisfying all entry criteria was 31% (95% CI 21 to 42). FCBG values decreased between baseline and study end (difference -3.7 mmol/L, 95% CI -6.5 to -0.8); 83% (95% CI 44 to 95) of ulcers healed by 24 weeks. FCBG correlated negatively with medication satisfaction. Ulcer area logarithm was most sensitive to FCBG changes, displaying significant negative correlation with HRQoL outcomes. Detecting a 30% between-group difference in this outcome (80% power, ?=5%) requires 220 participants per arm, achievable within 1 year with 15 centres similar to study setting. CONCLUSIONS:An adequately powered RCT requires cooperation between a large number of centres. Ulcer area logarithm should be primary endpoint. TRIAL REGISTRATION NUMBER:ANZCTR ACTRN12617001414303.

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Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.

Publications

Human CD133+ progenitor cells promote the healing of diabetic ischemic ulcers by paracrine stimulation of angiogenesis and activation of Wnt signaling.

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