Adipose-Derived Stromal Cells Seeded in Pullulan-Collagen Hydrogels Improve Healing in Murine Burns

• Published in: Tissue engineering. Part A 2021-06, Vol.27 (11-12), p.844-856
• Main Authors: Barrera, Janos, Trotsyuk, Artem, Maan, Zeshaan N, Bonham, Clark A, Larson, Madelyn R, Mittermiller, Paul A, Henn, Dominic, Chen, Kellen, Mays, Chyna J, Mittal, Smiti, Mermin-Bunnell, Alana M, Sivaraj, Dharshan, Jing, Serena, Rodrigues, Melanie, Kwon, Sun Hyung, Noishiki, Chikage, Padmanabhan, Jagannath, Jiang, Yuanwen, Niu, Simiao, Inayathullah, Mohammed, Rajadas, Jayakumar, Januszyk, Michael, Gurtner, Geoffrey C
• Format: Article
• Language: English
• Subjects: Burns; Cell therapy; Collagen; Dipeptidyl-peptidase IV; Flow cytometry; Gene expression; Hydrogels; Immunomodulation; Inflammation; Mesenchyme; Monocyte chemoattractant protein 1; Morbidity; Original Articles; Paracrine signalling; Public health; Pullulan; Regeneration; Regenerative medicine; Scars; SDF-1 protein; Stem cell transplantation; Stem cells; Stromal cells; Thermal injury; Tissue engineering; Transcription; Translation; Vascular endothelial growth factor; Wound healing
• ISSN: 1937-3341; 1937-335X
• DOI: 10.1089/ten.tea.2020.0320

Burn scars and scar contractures cause significant morbidity for patients. Recently, cell-based therapies have been proposed as an option for improving healing and reducing scarring after burn injury, through their known proangiogenic and immunomodulatory paracrine effects. Our laboratory has developed a pullulan-collagen hydrogel that, when seeded with mesenchymal stem cells (MSCs), improves cell viability and augments their proangiogenic capacity in vivo . Concurrently, recent research suggests that prospective isolation of cell subpopulations with desirable transcriptional profiles can be used to further improve cell-based therapies. In this study, we examined whether adipose-derived stem cell (ASC)-seeded hydrogels could improve wound healing following thermal injury using a murine contact burn model. Partial thickness contact burns were created on the dorsum of mice. On days 5 and 10 following injury, burns were debrided and received either ASC hydrogel, ASC injection alone, hydrogel alone, or no treatment. On days 10 and 25, burns were harvested for histologic and molecular analysis. This experiment was repeated using CD26 + /CD55 + FACS-enriched ASCs to further evaluate the regenerative potential of ASCs in wound healing. ASC hydrogel-treated burns demonstrated accelerated time to reepithelialization, greater vascularity, and increased expression of the proangiogenic genes MCP-1, VEGF, and SDF-1 at both the mRNA and protein level. Expression of the profibrotic gene Timp1 and proinflammatory gene Tnfa was downregulated in ASC hydrogel-treated burns. ASC hydrogel-treated burns exhibited reduced scar area compared to hydrogel-treated and control wounds, with equivalent scar density. CD26 + /CD55 + ASC hydrogel treatment resulted in accelerated healing, increased dermal appendage count, and improved scar quality with a more reticular collagen pattern. Here we find that ASC hydrogel therapy is effective for treating burns, with demonstrated proangiogenic, fibromodulatory, and immunomodulatory effects. Enrichment for CD26 + /CD55 + ASCs has additive benefits for tissue architecture and collagen remodeling postburn injury. Research is ongoing to further facilitate clinical translation of this promising therapeutic approach.