Sweat gland regeneration: Current strategies and future opportunities

Chen, Runkai; Zhu, Ziying; Ji, Shuaifei; Geng, Zhijun; Hou, Qi; Sun, Xiaoyan; Fu, Xiaobing

doi:10.1016/j.biomaterials.2020.120201

Cited by 24 publications

(21 citation statements)

References 201 publications

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“…After SG induction, SG-like cells in the scaffold showed a round and condensate appearance ( Figure 1i ), which proved the differentiation of MSCs into SG-like cells at the morphological level. KRT 18 and KRT19 are 2 structural marker proteins expressed in luminal cells of SGs [ 22 ]. As with HF, KRT17 is the structural marker protein while alkaline phosphatase is the functional protein expressed in the hair shaft [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

Using bioprinting and spheroid culture to create a skin model with sweat glands and hair follicles

et al. 2021

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Background Sweat glands (SGs) and hair follicles (HFs) are two important cutaneous appendages that play crucial roles in homeostatic maintenance and thermoregulation, and their interaction is involved in wound healing. SGs can be regenerated from mesenchymal stem cell-laden 3D bioprinted scaffolds, based on our previous studies, whereas regeneration of HFs could not be achieved in the same model. Due to the lack of an in vitro model, the underlying molecular mechanism of the interaction between SGs and HFs in regeneration could not be fully understood. The purpose of the present study was to establish an in vitro model of skin constructs with SGs and HFs and explore the interaction between these two appendages in regeneration. Methods To investigate the interaction effects between SGs and HFs during their regeneration processes, a combined model was created by seeding HF spheroids on 3D printed SG scaffolds. The interaction between SG scaffolds and HF spheroids was detected using RNA expression and immunofluorescence staining. The effects of microenvironmental cues on SG and HF regeneration were analysed by altering seed cell types and plantar dermis homogenate in the scaffold. Results According to this model, we overcame the difficulties in simultaneously inducing SG and HF regeneration and explored the interaction effects between SG scaffolds and HF spheroids. Surprisingly, HF spheroids promoted both SG and HF differentiation in SG scaffolds, while SG scaffolds promoted SG differentiation but had little effect on HF potency in HF spheroids. Specifically, microenvironmental factors (plantar dermis homogenate) in SG scaffolds effectively promoted SG and HF genesis in HF spheroids, no matter what the seed cell type in SG scaffolds was, and the promotion effects were persistent. Conclusions Our approach elucidated a new model for SG and HF formation in vitro and provided an applicable platform to investigate the interaction between SGs and HFs in vitro. This platform might facilitate 3D skin constructs with multiple appendages and unveil the spatiotemporal molecular program of multiple appendage regeneration.

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Section: Resultsmentioning

confidence: 99%

Using bioprinting and spheroid culture to create a skin model with sweat glands and hair follicles

et al. 2021

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“…In addition, the WNT signaling pathway and the EDA/EDAR axis together guide SwG morphogenesis. For example, LEF1 binds the 1.6-kb DNA sequence upstream of the EDA transcriptional initiation site and further activates the EDA/EDAR signaling pathway [ 33 ]. The bone morphogenetic protein (BMP) signaling pathway also mediates a switch to SG fate in skin.…”

Section: Discussionmentioning

confidence: 99%

Small molecules facilitate single factor-mediated sweat gland cell reprogramming

Zhou

Sun

et al. 2022

Military Med Res

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Background 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. Methods 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. Results 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. Conclusion 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.

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“…It has been reported that WNT10A mutations account for 16% of HED [28]. In addition, there exists an inseparable linkage between the WNT signaling pathway and the EDA/EDAR axis in guiding SwG morphogenesis, for instance, LEF1 could bind to the 1.6-kb DNA sequence upstream of the EDA transcriptional initiation site and further activate the EDA/EDAR signaling pathway [29]. Bone morphogenetic protein (BMP) signaling pathway also mediates a switch in SG fate in skin.…”

Section: Discussionmentioning

confidence: 99%

Small Molecules Facilitate Single Factor-Mediated Sweat Gland Cell Reprogramming

Zhou

et al. 2021

Preprint

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Background: Large skin defect caused severe disruption to the overall skin structure and irreversible damage of sweat gland (SG), resulting in destroy of physiological function of the skin. Reprogramming fibroblasts into sweat gland lineages may provide a promising strategy to obtain the desirable cell types for functional repair and regeneration of damaged skin. Methods: A direct reprogramming strategy of single factor ectodermal dysplasia antigen (EDA) in combination with small molecule cocktails promoting cell-fate conversion to regenerate SG cells from human dermal fibroblasts (HDFs) was developed. Quantitative PCR (qPCR), flow cytometry, calcium activity analysis, immunocytochemical analyses and starch-iodine sweat tests were used to characterize the phenotype, gene expression and function features of the induced sweat gland cells (iSGCs). Results: EDA overexpression drove HDFs toward SG lineages, and HDFs transfected with EDA acquired sweat gland cell phenotype in sweat gland conditional medium (SGM). Small-molecule cocktails favoring SG lineages greatly accelerated the SG fate program in SGM-treated HDF-EDA cells and further induced the regeneration of iSGCs. The HDFs-derived iSGCs exhibited similar phenotypical and functional features of native sweat gland cells. Eventually, in vivo transplantation experiment confirmed that iSGCs had the ability to regenerate SG structurally and functionally.Conclusion: We developed a SG reprogramming strategy to generate functional iSGCs from HDFs by using single factor EDA in combination with small molecules. The generation of iSGCs has important implications for in situ skin regeneration with restoration of sweat glands in the future.

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Sweat gland regeneration: Current strategies and future opportunities

Cited by 24 publications

References 201 publications

Using bioprinting and spheroid culture to create a skin model with sweat glands and hair follicles

Using bioprinting and spheroid culture to create a skin model with sweat glands and hair follicles

Small molecules facilitate single factor-mediated sweat gland cell reprogramming

Small Molecules Facilitate Single Factor-Mediated Sweat Gland Cell Reprogramming

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