Label Retaining Cells (LRCs) with Myoepithelial Characteristic from the Proximal Acinar Region Define Stem Cells in the Sweat Gland

Abstract

Slow cycling is a common feature shared among several stem cells (SCs) identified in adult tissues including hair follicle and cornea. Recently, existence of unipotent SCs in basal and lumenal layers of sweat gland (SG) has been described and label retaining cells (LRCs) have also been localized in SGs; however, whether these LRCs possess SCs characteristic has not been investigated further. Here, we used a H2BGFP LRCs system for in vivo detection of infrequently dividing cells. This system allowed us to specifically localize and isolate SCs with label-retention and myoepithelial characteristics restricted to the SG proximal acinar region. Using an alternative genetic approach, we demonstrated that SG LRCs expressed keratin 15 (K15) in the acinar region and lineage tracing determined that K15 labeled cells contributed long term to the SG structure but not to epidermal homeostasis. Surprisingly, wound healing experiments did not activate proximal acinar SG cells to participate in epidermal healing. Instead, predominantly non-LRCs in the SG duct actively divided, whereas the majority of SG LRCs remained quiescent. However, when we further challenged the system under more favorable isolated wound healing conditions, we were able to trigger normally quiescent acinar LRCs to trans-differentiate into the epidermis and adopt its long term fate. In addition, dissociated SG cells were able to regenerate SGs and, surprisingly, hair follicles demonstrating their in vivo plasticity. By determining the gene expression profile of isolated SG LRCs and non-LRCs in vivo, we identified several Bone Morphogenetic Protein (BMP) pathway genes to be up-regulated and confirmed a functional requirement for BMP receptor 1A (BMPR1A)-mediated signaling in SG formation. Our data highlight the existence of SG stem cells (SGSCs) and their primary importance in SG homeostasis. It also emphasizes SGSCs as an alternative source of cells in wound healing and their plasticity for regenerating different skin appendages.

Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration

“…4 B and D) (23, 24). Collectively, our findings draw similarities for a key role of Bmpr1a-mediated signaling for the proper adoption of nail fate and differentiation similar to findings reported in hair follicle and sweat gland appendage development (2,17,20).…”

“…Previous reports have described the presence of LRCs within the nail Mx (11); however, we observed a clear distinction between slow-cycling, nail LRCs in the PF and the actively dividing Mx cells after only 1 wk of chase ( During Normal Nail Homeostasis, K15 + Nail Proximal Fold Cells Demonstrate Bifunctionality Toward the Nail Structure and Peri-Nail Epidermis. Because slow-cycling LRCs often possess SCs character, we performed immunofluorescence directed against the skin stem cell marker, keratin 15 (K15), expressed by both hair follicle and sweat gland SCs (2,3,12) and detected K15 + expression in the majority of PF LRCs (Fig. 2G).…”

“…The skin contains a number of associated appendages such as hair follicles, sebaceous glands, sweat glands, and nails that display different modes of renewal, regeneration, and stem cell (SC) homeostatic dynamics during normal wear and tear (1). For example, the epidermis undergoes continual renewal, hair follicles undergo episodic regeneration, and sweat glands display little turnover as demonstrated by the presence of quiescent label-retaining stem cells in vivo (2,3). Moreover, nails exhibit continuous growth under physiological conditions and can fully regenerate upon removal.…”

“…Previously, the slow cycling, label-retaining cells (LRCs) characteristic has been successfully used to identify SCs in various organs including the hair follicle, cornea, and sweat gland; however, existence of a quiescent SC population in continuously growing nails has not been revealed so far (2,3,(5)(6)(7). Here, we aim to identify the location of LRCs in mouse nails, characterize their molecular features, and evaluate their stem cell potential in vivo.…”

Role of regeneration in tissue repairing and therapies

“…Wound healing is a complex and dynamic process of replacing devitalized and missing cellular structures and tissue layers [104]. Normally, this process completes in 3 or 4 distinct phases i.e., inflammatory, fibroblastic, and maturation [3].…”