Extracellular caspase-1 regulates hair follicle stem cell migration during wound-healing

• Published in: bioRxiv
• Main Authors: Ghosh, Subhasri, Hegde, Akshay, Ananthan, Akhil Shp, Kataria, Sunny, Pincha, Neha, Dutta, Anupam, Dutta, Abhik, Athreya, Srilekha, Khedkar, Sneha Uday, Dey, Rakesh, Bhosale, Aishwarya, Jamora, Colin
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 30.09.2022
• Subjects: Caspase; Caspase-1; Cell migration; Chemotaxis; Homeostasis; Hyperplasia; Inflammasomes; Inflammatory diseases; Keratinocytes; Metastases; Skin; Stem cells; Wound healing
• DOI: 10.1101/548529

Migration of stem cells from one niche to another is a fundamental behavior 1 observed during tissue morphogenesis, homeostasis, and repair. A common thread running throughout these phenomena is the ability of stem cells to sense their environmental cues that, in turn, regulate their spatiotemporal localization with amazing precision. Perturbations of such cellular responses underlie a spectrum of pathologies 2,3 ranging from developmental defects, tumor metastasis and ineffective wound closure. In somatic tissues, the wound-healing process is a paradigm of the directed migration of various stem cell pools to the site of injury where they differentiate to replenish lost or damaged cells. While there has been substantial investment and progress in understanding the lineage trajectory of stem cells once they reach their destination, comparatively little is understood regarding the mechanisms guiding their chemotactic journey to the wound site. In the context of the skin, it has been shown nearly two decades ago that wounding activates various local epithelial stem cell pools, including multipotent hair follicle stem cells, to infiltrate the epidermis where they participate in the 4,5 reconstruction of the damaged tissue that coax these cells out of their hair follicle niche to the damaged epidermis has proven to be an intractable problem to solve. Using both an excisional wound and genetic mouse models of wound healing, we discovered that wounded keratinocytes secrete the enzyme Caspase-1. This protein is classically known as a critical component of the cytosolic macromolecular complex called an inflammasome that mediates the unconventional 6 secretion of various cytokines including IL-1α . Surprisingly, we find that the released caspase-1 itself has a non-canonical role in the extracellular milieu. Through the Caspase Activation Recruitment Domain (CARD) of caspase-1, this protein is sufficient to initiate chemotaxis of hair follicle stem cells into the epidermis. The secretion of caspase-1 has also been documented in many other pathological scenarios 7,8 and we observed that the migration of HFSCs into the epidermis following UV irradiation of the skin is also caspase-1 dependent. Uncovering this novel function of Caspase-1 facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases. Competing Interest Statement The authors have declared no competing interest. Footnotes * Additional experiments have been performed and authors added