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Angiogenin Released from ABCB5⁺ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

ABSTRACT: Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5⁺ stromal precursors at the edge of nonhealing diabetic wounds in a murine db/db model, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5⁺ stromal precursors. This compensates for the profoundly reduced angiogenin expression in nontreated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5⁺ stromal precursors before injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice, implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining stromal precursors-based therapies of nonhealing diabetic foot ulcers and other pathologies with impaired angiogenesis.

SUBMITTER: Singh K

PROVIDER: S-EPMC9676024 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Angiogenin Released from ABCB5<sup>+</sup> Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

Singh Karmveer K Maity Pallab P Koroma Albert Kallon AK Basu Abhijit A Pandey Rajeev Kumar RK Vander Beken Seppe S Haas Philipp P Krug Linda L Hainzl Adelheid A Sindrilaru Anca A Pfeiffer Christiane C Wlaschek Meinhard M Frank Natasha Y NY Frank Markus H MH Ganss Christoph C Bánvölgyi András A Wikonkál Norbert N Eming Sabine S Pastar Irena I Tomic-Canic Marjana M Kluth Mark A MA Scharffetter-Kochanek Karin K

The Journal of investigative dermatology 20211120 6

Severe angiopathy is a major driver for diabetes-associated secondary complications. Knowledge on the underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5<sup>+</sup> stromal precursors at the edge of nonhealing diabetic wounds in a murine db/db model, closely mirroring human type 2 diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogen ...[more]

PMID: 34808236

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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.

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Angiogenin Released from ABCB5⁺ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

Publications

Angiogenin Released from ABCB5<sup>+</sup> Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

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Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

Publications

Angiogenin Released from ABCB5<sup>+</sup> Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Angiogenin Released from ABCB5⁺ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis.