脂肪来源的间充质干细胞通过 CCL5 和 CXCL12 抑制增生性瘢痕成纤维细胞增殖。

Adipose-derived mesenchymal stem cells suppress fibroblast proliferation of hypertrophic scar through CCL5 and CXCL12.

机构信息

Department of Burns and Plastic Surgery, Shenzhen Hospital of Southern Medical University, No.1333, Xinhu Road, Baoan District, Shenzhen, 518000, Guangdong, China.

Department of Orthopaedics, Shenzhen Hospital of Southern Medical University, Shenzhen, 518000, Guangdong, China.

出版信息

Arch Dermatol Res. 2024 Aug 17;316(8):527. doi: 10.1007/s00403-024-03289-2.

DOI:10.1007/s00403-024-03289-2

PMID:39153095

Abstract

BACKGROUND AND OBJECTIVE

Adipose-derived mesenchymal stem cells (ADSCs) can accelerate wound healing, reduce scar formation, and inhibit hypertrophic scar (HTS). ADSCs can secrete a large amount of CCL5, and CCL5 has been proved to be pro-inflammatory and pro-fibrotic. CXCL12 (SDF-1) is a key chemokine that promotes stem cell migration and survival. Therefore, this study selected normal skin and HTS conditioned medium to simulate different microenvironments, and analyzed the effects of different microenvironments on the expression of CCL5 and CXCL12 in human ADSCs (hADSCs).

MATERIALS AND METHODS

hADSCs with silenced expression of CCL5 and CXCL12 were co-cultured with hypertrophic scar fibroblasts to verify the effects of CCL5 and CXCL12 in hADSCs on the proliferation ability of hypertrophic scar fibroblasts. A mouse model of hypertrophic scar was established to further confirm the effect of CCL5 and CXCL12 in hADSCs on hypertrophic scar formation.

RESULTS

CCL5 level was found to be significantly high in hADSCs cultured in HTS conditioned medium. CXCL12 in HTS group was prominently lowly expressed compared with the normal group. Inhibition of CCL5 in hADSCs enhanced the effects of untreated hADSCs on proliferation of HTS fibroblasts while CXCL12 knockdown exerted the opposite function. Inhibition of CCL5 in hADSCs increased the percentage of HTS fibroblasts in the G0/G1 phase while down-regulation of CXCL12 decreased those. Meanwhile, the down-regulated levels of fibroblast markers including collagen I, collagen III, and α-SMA induced by CCL5 knockdown were significantly up-regulated by CXCL12 inhibition. hADSCs alleviate the HTS of mice through CCL5 and CXCL12.

CONCLUSION

In summary, our results demonstrated that hADSCs efficiently cured HTS by suppressing proliferation of HTS fibroblasts, which may be related to the inhibition of CXCL12 and elevation of CCL5 in hADSCs, suggesting that hADSCs may provide an alternative therapeutic approach for the treatment of HTS.

摘要

背景与目的

脂肪间充质干细胞（ADSCs）可以加速伤口愈合、减少疤痕形成并抑制增生性瘢痕（HTS）。ADSCs 可以大量分泌 CCL5，CCL5 已被证明具有促炎和促纤维化作用。CXCL12（SDF-1）是一种关键趋化因子，可促进干细胞迁移和存活。因此，本研究选择正常皮肤和 HTS 条件培养基来模拟不同的微环境，并分析不同微环境对人 ADSCs（hADSCs）中 CCL5 和 CXCL12 表达的影响。

材料与方法

沉默 CCL5 和 CXCL12 的 hADSCs 与增生性瘢痕成纤维细胞共培养，以验证 hADSCs 中 CCL5 和 CXCL12 对增生性瘢痕成纤维细胞增殖能力的影响。建立增生性瘢痕的小鼠模型，进一步证实 hADSCs 中 CCL5 和 CXCL12 对增生性瘢痕形成的影响。

结果

在 HTS 条件培养基中培养的 hADSCs 中发现 CCL5 水平显著升高。HTS 组的 CXCL12 表达明显低于正常组。hADSCs 中 CCL5 的抑制增强了未经处理的 hADSCs 对 HTS 成纤维细胞增殖的影响，而 CXCL12 的敲低则发挥了相反的作用。hADSCs 中 CCL5 的抑制增加了 HTS 成纤维细胞处于 G0/G1 期的比例，而下调 CXCL12 则降低了该比例。同时，CCL5 敲低诱导的成纤维细胞标志物包括胶原 I、胶原 III 和α-SMA 的下调水平，通过 CXCL12 抑制明显上调。hADSCs 通过 CCL5 和 CXCL12 减轻小鼠的 HTS。