Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice.

Autor: Yang HY; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Fierro F; Department of Cell Biology and Human Anatomy, University of California, Davis, Sacramento, California, USA.; Stem Cell Program, Department of Internal Medicine, University of California, Davis, Davis, California, USA., So M; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Yoon DJ; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Nguyen AV; Department of Dermatology, University of California, Davis, Sacramento, California, USA.; Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, California, USA., Gallegos A; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Bagood MD; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Rojo-Castro T; Department of Biological Sciences, California State University, Sacramento, Sacramento, California, USA., Alex A; Department of Biological Sciences, California State University, Sacramento, Sacramento, California, USA., Stewart H; Stem Cell Program, Department of Internal Medicine, University of California, Davis, Davis, California, USA., Chigbrow M; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Dasu MR; Department of Dermatology, University of California, Davis, Sacramento, California, USA., Peavy TR; Department of Biological Sciences, California State University, Sacramento, Sacramento, California, USA., Soulika AM; Department of Dermatology, University of California, Davis, Sacramento, California, USA.; Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, California, USA., Nolta JA; Stem Cell Program, Department of Internal Medicine, University of California, Davis, Davis, California, USA., Isseroff RR; Department of Dermatology, University of California, Davis, Sacramento, California, USA.; Dermatology Section, VA Northern California Health Care System, Mather, California, USA.
Jazyk: angličtina
Zdroj: Stem cells translational medicine [Stem Cells Transl Med] 2020 Nov; Vol. 9 (11), pp. 1353-1364. Date of Electronic Publication: 2020 Jul 28.
DOI: 10.1002/sctm.19-0380
Abstrakt: Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)-based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia-preconditioned, allogeneic human MSCs combined with the beta-adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 μM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 10 5  cells/cm 2 on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7-day treatment, accumulative steady-state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro-inflammatory cytokines IL-1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti-inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5-fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.
(© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)
Databáze: MEDLINE
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