Adipose-Derived Stromal Cells Seeded in Pullulan-Collagen Hydrogels Improve Healing in Murine Burns
Adipose-Derived Stromal Cells Seeded in Pullulan-Collagen Hydrogels Improve Healing in Murine Burns
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DOI：
10.1089/ten.tea.2020.0320
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发表时间：
2021-05-27
影响因子：
4.1
通讯作者：
Gurtner, Geoffrey C.
中科院分区：
文献类型：
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作者：
Barrera, Janos A.;Trotsyuk, Artem A.;Gurtner, Geoffrey C.
烧伤疤痕和疤痕挛缩会导致患者的严重发病率。最近，基于细胞的疗法已被提出作为改善烧伤后愈合和减少疤痕的一种选择，通过其已知的促血管生成和免疫调节旁分泌作用。我们的实验室已经开发出一种普鲁兰多糖-胶原蛋白水凝胶，当与间充质干细胞（MSC）接种时，可提高细胞活力并增强其体内促血管生成能力。同时，最近的研究表明，具有所需转录谱的细胞亚群的前瞻性分离可用于进一步改善基于细胞的疗法。在这项研究中，我们研究了脂肪干细胞（ASC）接种的水凝胶是否可以使用小鼠接触性烧伤模型改善热损伤后的伤口愈合。在小鼠背部造成部分厚度接触性烧伤。受伤后第5天和第10天，对烧伤进行清创，并接受ASC水凝胶、单独注射ASC、单独注射水凝胶或不接受治疗。在第10天和第25天，收获烧伤用于组织学和分子分析。使用富含CD 26（+）/CD 55（+）FACS的ASC重复该实验，以进一步评估ASC在伤口愈合中的再生潜力。ASC水凝胶治疗的烧伤表现出加快的时间，再上皮化，更大的血管，并增加表达的促血管生成基因MCP-1，VEGF和SDF-1在mRNA和蛋白质水平。ASC水凝胶治疗烧伤后，促纤维化基因Timp 1和促炎基因Tnfa的表达下调。ASC水凝胶治疗的烧伤与水凝胶治疗的和对照伤口相比，瘢痕面积减少，瘢痕密度相等。CD 26（+）/CD 55（+）ASC水凝胶治疗导致愈合加速，皮肤附件计数增加，瘢痕质量改善，胶原蛋白模式更加网状。在这里，我们发现ASC水凝胶疗法对治疗烧伤是有效的，具有已证实的促血管生成、纤维调节和免疫调节作用。CD 26（+）/CD 55（+）ASC的富集对烧伤后的组织结构和胶原蛋白重塑具有额外的益处。目前正在进行研究，以进一步促进这种有前途的治疗方法的临床转化。影响声明烧伤仍然是一个重大的公共卫生负担。干细胞疗法作为治疗烧伤的一种有前途的方法已经引起了人们的注意。我们已经开发了一种普鲁兰多糖胶原仿生水凝胶支架，可以与脂肪来源的干细胞（ASCs）接种。我们评估了我们的支架在鼠接触性烧伤模型中的递送和活性。我们的研究结果表明，局部递送ASC水凝胶治疗是治疗烧伤伤口的一种有前途的方法，具有快速临床转化的潜力。我们相信我们的工作将对水凝胶疗法和再生医学产生广泛的影响，并将引起一般科学界的兴趣。
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.Impact statementBurns remain a significant public health burden. Stem cell therapy has gained attention as a promising approach for treating burns. We have developed a pullulan-collagen biomimetic hydrogel scaffold that can be seeded with adipose-derived stem cells (ASCs). We assessed the delivery and activity of our scaffold in a murine contact burn model. Our results suggest that localized delivery of ASC hydrogel treatment is a promising approach for the treatment of burn wounds, with the potential for rapid clinical translation. We believe our work will have broad implications for both hydrogel therapeutics and regenerative medicine and will be of interest to the general scientific community.