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Direct reprogramming of epidermal cells toward sweat gland-like cells by defined factors.

ABSTRACT: Several studies have reported inducing adult cells into sweat gland-like cells; however, slow transition and low efficiency limit the potential for cell-based treatment. Here, we show that overexpression of the transcription factor FoxC1 was sufficient to reprogram epidermal cells to induced functional sweat gland-like cells (iSGCs). The iSGCs expressing secreting-related genes, had a global gene expression profile between fetal SGCs (P5) and adult SGCs (P28). Moreover, iSGCs transplanted into the burn mice model facilitated wound repair and sweat gland regeneration. We further demonstrated that the Foxc1 upregulated BMP5 transcription and BMP5 is responsible for the cell-type transition. Collectively, this study shows that lineage reprogramming of epidermal cells into iSGCs provides an excellent cell source and a promising regenerative strategy for anhidrosis and hypohidrosis.

SUBMITTER: Yao B

PROVIDER: S-EPMC6426881 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Direct reprogramming of epidermal cells toward sweat gland-like cells by defined factors.

Yao Bin B Xie Jiangfan J Liu Nanbo N Hu Tian T Song Wei W Huang Sha S Fu Xiaobing X

Cell death & disease 20190320 4

Several studies have reported inducing adult cells into sweat gland-like cells; however, slow transition and low efficiency limit the potential for cell-based treatment. Here, we show that overexpression of the transcription factor FoxC1 was sufficient to reprogram epidermal cells to induced functional sweat gland-like cells (iSGCs). The iSGCs expressing secreting-related genes, had a global gene expression profile between fetal SGCs (P5) and adult SGCs (P28). Moreover, iSGCs transplanted into t ...[more]

PMID: 30894517

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Project description:Large skin defects severely disrupt the overall skin structure and can irreversibly damage sweat glands (SG), thus impairing the skin's physiological function. This study aims to develop a stepwise reprogramming strategy to convert fibroblasts into SG lineages, which may provide a promising method to obtain desirable cell types for the functional repair and regeneration of damaged skin. The expression of the SG markers cytokeratin 5 (CK5), cytokeratin 10 (CK10), cytokeratin 18 (CK18), carcino-embryonic antigen (CEA), aquaporin 5 (AQP5) and α-smooth muscle actin (α-SMA) was assessed with quantitative PCR (qPCR), immunofluorescence and flow cytometry. Calcium activity analysis was conducted to test the function of induced SG-like cells (iSGCs). Mouse xenograft models were also used to evaluate the in vivo regeneration of iSGCs. BALB/c nude mice were randomly divided into a normal group, SGM treatment group and iSGC transplantation group. Immunocytochemical analyses and starch-iodine sweat tests were used to confirm the in vivo regeneration of iSGCs. EDA overexpression drove HDF conversion into iSGCs in SG culture medium (SGM). qPCR indicated significantly increased mRNA levels of the SG markers CK5, CK18 and CEA in iSGCs, and flow cytometry data demonstrated (4.18 ± 0.04)% of iSGCs were CK5 positive and (4.36 ± 0.25)% of iSGCs were CK18 positive. The addition of chemical cocktails greatly accelerated the SG fate program. qPCR results revealed significantly increased mRNA expression of CK5, CK18 and CEA in iSGCs, as well as activation of the duct marker CK10 and luminal functional marker AQP5. Flow cytometry indicated, after the treatment of chemical cocktails, (23.05 ± 2.49)% of iSGCs expressed CK5+ and (55.79 ± 3.18)% of iSGCs expressed CK18+, respectively. Calcium activity analysis indicated that the reactivity of iSGCs to acetylcholine was close to that of primary SG cells [(60.79 ± 7.71)% vs. (70.59 ± 0.34)%, ns]. In vivo transplantation experiments showed approximately (5.2 ± 1.1)% of the mice were sweat test positive, and the histological analysis results indicated that regenerated SG structures were present in iSGCs-treated mice. We developed a SG reprogramming strategy to generate functional iSGCs from HDFs by using the single factor EDA in combination with SGM and small molecules. The generation of iSGCs has important implications for future in situ skin regeneration with SG restoration.

Dataset Information

Direct reprogramming of epidermal cells toward sweat gland-like cells by defined factors.

Publications

Direct reprogramming of epidermal cells toward sweat gland-like cells by defined factors.

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