PMID- 33422138 OWN - NLM STAT- MEDLINE DCOM- 20210705 LR - 20240330 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 12 IP - 1 DP - 2021 Jan 9 TI - Human foreskin-derived dermal stem/progenitor cell-conditioned medium combined with hyaluronic acid promotes extracellular matrix regeneration in diabetic wounds. PG - 49 LID - 10.1186/s13287-020-02116-5 [doi] LID - 49 AB - BACKGROUND: Diabetic wounds remain a challenging clinical problem, which requires further treatment development. Published data showed that dermis-derived stem/progenitor cells (DSPCs) display superior wound healing in vitro. The beneficial effects of DSPCs are mediated through paracrine secretion, which can be obtained from conditioned medium (CM). Hyaluronic acid (HA) is especially suitable for skin regeneration and delivering bioactive molecules in CM. This study investigated the effect of human foreskin-derived dermal stem/progenitor cell (hFDSPC)-CM combined with HA on a diabetic mouse model and relevant mechanism in vitro. METHODS: hFDSPCs and human adipose-derived stem cells (hADSCs) were identified, and the respective CM was prepared. PBS, HA, hFDSPC-CM combined with HA, or hADSC-CM combined with HA was topically applied to mice. HE, CD31, CD68, CD86, and CD206 staining was performed to evaluate gross wound condition, angiogenesis, and inflammation, respectively. Masson and Picrosirius red staining was performed to evaluate collagen deposition and maturation. The effects of hFDSPC-CM and hADSC-CM on human keratinocyte cells (HaCaT) and fibroblasts were evaluated in vitro using CCK-8 and EdU assays to determine cell viability and proliferation, respectively. The scratch assay was performed to evaluate cell migration. Tube formation assay was performed on human umbilical vein endothelial cells (HUVECs) to confirm angiogenesis. Extracellular matrix (ECM) metabolic balance-related genes and proteins, such as collagen I (COL 1), collagen III (COL 3), fibronectin (FN), alpha-SMA, matrix metalloproteinases 1 (MMP-1), matrix metalloproteinases 3 (MMP-3), and transforming growth factor-beta 1 (TGF-beta1), were analysed. RESULTS: hFDSPC-CM combined with HA showed superior wound closure rate over hADSC-CM. Histologically, the hFDSPC-CM combined with HA group showed significantly improved re-epithelialisation, angiogenesis, anti-inflammation, collagen regeneration, and maturation compared to hADSC-CM combined with HA group. In vitro assays revealed that hFDSPC-CM displayed significant advantages on cell proliferation, migration, and ECM regeneration through a TGF-beta/Smad signalling pathway compared with hADSC-CM. CONCLUSIONS: hFDSPC-CM combined with HA was superior for treating diabetic wounds. The underlying mechanism may promote proliferation and migration of epidermal cells with fibroblasts, thus leading to ECM deposition and remodelling. Reduced inflammation may be due to the above-mentioned mechanism. FAU - Xin, Yu AU - Xin Y AD - Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China. FAU - Xu, Peng AU - Xu P AD - Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China. AD - Shanghai Tissue Engineering Key Laboratory, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Wang, Xiangsheng AU - Wang X AD - Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China. AD - Shanghai Tissue Engineering Key Laboratory, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China. FAU - Chen, Yunsheng AU - Chen Y AD - Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China. FAU - Zhang, Zheng AU - Zhang Z AD - Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China. zhangzheng958@163.com. FAU - Zhang, Yixin AU - Zhang Y AD - Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai, 200011, China. zhangyixin6688@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210109 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Culture Media, Conditioned) RN - 9004-61-9 (Hyaluronic Acid) SB - IM MH - Animals MH - Culture Media, Conditioned/pharmacology MH - *Diabetes Mellitus MH - Extracellular Matrix MH - Fibroblasts MH - Foreskin MH - Humans MH - *Hyaluronic Acid MH - Male MH - Mice MH - Stem Cells PMC - PMC7796620 OTO - NOTNLM OT - Conditioned medium OT - Dermal stem/progenitor cells OT - Diabetic wound healing OT - Extracellular matrix OT - Human foreskin COIS- The authors declare that they have no competing interests. EDAT- 2021/01/11 06:00 MHDA- 2021/07/06 06:00 PMCR- 2021/01/09 CRDT- 2021/01/10 20:25 PHST- 2020/06/20 00:00 [received] PHST- 2020/12/22 00:00 [accepted] PHST- 2021/01/10 20:25 [entrez] PHST- 2021/01/11 06:00 [pubmed] PHST- 2021/07/06 06:00 [medline] PHST- 2021/01/09 00:00 [pmc-release] AID - 10.1186/s13287-020-02116-5 [pii] AID - 2116 [pii] AID - 10.1186/s13287-020-02116-5 [doi] PST - epublish SO - Stem Cell Res Ther. 2021 Jan 9;12(1):49. doi: 10.1186/s13287-020-02116-5.