The lysosomal trafficking regulator is necessary for normal wound healing

Abstract

Non-healing wounds are a major threat to public health throughout the United States. Tissue healing is complex multifactorial process that requires synchronicity of several cell types. Endolysosomal trafficking, which contributes to various cell functions from protein degradation to plasma membrane repair, is an understudied process in the context of wound healing. The lysosomal trafficking regulator protein (LYST) is an essential protein of the endolysosomal system through an indeterminate mechanism.In this study, we examine the impact of impaired LYST function both in vitro with primary LYST mutant fibroblasts as well as in vivo with an excisional wound model. The wound model shows that LYST mutant mice have impaired wound healing in the form of delayed epithelialization and collagen deposition, independent of macrophage infiltration and polarisation. We show that LYST mutation confers a deficit in MCP-1, IGF-1, and IGFBP-2 secretion in beige fibroblasts, which are critical factors in normal wound healing. Identifying the mechanism of LYST function is important for understanding normal wound biology, which may facilitate the development of strategies to address problem wound healing.

Mesenchymal stem cell-derived secretomes-enriched alginate/ extracellular matrix hydrogel patch accelerates skin wound healing

“…The HGF would facilitate re-epithelialization, granulation tissue formation, and angiogenesis [ 33 ]. The insulin-like growth factor (IGF) activated by IGFBP is also known to promote cell proliferation and re-epithelialization [ 34 , 35 ]. In addition, the inflammatory cytokines, IL-6 and IL-8 are closely related to re-epithelialization and keratinocyte migration [ 18 ].…”

The lysosomal trafficking regulator “LYST”: an 80-year traffic jam

“…Lysosomal origin was also confirmed in various cell types including beige osteoclasts, gastric chief cells, parietal cells, and renal proximal convoluted tubal cells with enlarged granules (119)(120)(121). Recent studies consistently affirmed the identity of the enlarged inclusions using specific lysosomal markers including lysosomal-associated membrane protein-1 (LAMP-1), LAMP-2, and Rab7 (40,64,87,(122)(123)(124).…”

“…Fibroblasts also provided the foundation for investigating LYST in conditions beyond CHS. Cutaneous wound healing studies showed that LYST is an important regulator of secretory exocytosis by fibroblasts, which confer deficits in MCP-1, IGF-1, and IGFBP-2 secretion when LYST is mutated ( 40 ). Such insights into fibroblast behavior underscore the complexity of LYST’s impact, paving the way for broader implications in various physiological processes and pathological conditions.…”

“…These advancements provided more clues for its involvement in a myriad of cellular processes. Over the past decade alone, LYST has been linked to human health outside of CHS through connections to cancer and wound healing (33)(34)(35)(36)(37)(38)(39)(40).…”