Role of collagen VI in peripheral nerves and wound-induced hair regrowth

Collagen VI is an extracellular matrix (ECM) molecule dynamically expressed in a variety of tissues, including peripheral nerves and skin. However, the role of collagen VI in the peripheral nervous system (PNS) and hair follicle growth is yet unknown. The main focus of my PhD study was to investigate the role and the underlying mechanisms of collagen VI in peripheral nerve myelination and function, in PNS regeneration, as well as in wound-induced hair growth. During the first year of my PhD, I focused on investigating the phenotype of peripheral nerve myelination and function in collagen VI null (Col6a1–/–) mice. The data shows that Schwann cells, but not axons, contribute to collagen VI deposition in peripheral nerves. Lack of collagen VI in Col6a1–/– mice leads to hypermyelination via multiple signaling pathways, disorganized C-fibers in the PNS, impaired nerve conduction velocity, and sensorimotor dysfunction. These findings indicate that that collagen VI is a critical component of PNS contributing to the structural integrity and proper function of peripheral nerves. The second part of my PhD work focused on investigating the role of collagen VI in PNS under pathological conditions using nerve crush injury models, and revealed a novel mechanism of this ECM protein in modulating macrophage function. The results show that collagen VI is critical for macrophage migration and polarization during peripheral nerve regeneration. Nerve injury induces a robust upregulation of collagen VI, whereas lack of collagen VI in Col6a1–/– mice delays peripheral nerve regeneration. In vitro studies demonstrated that collagen VI promotes macrophage migration and polarization via AKT and PKA pathways. Col6a1–/– macrophages exhibit impaired migration abilities and reduced anti-inflammatory (M2) phenotype polarization, but are prone to skewing towards pro-inflammatory (M1) phenotype. In vivo, macrophage recruitment and M2 polarization are impaired in Col6a1–/– mice after nerve injury. The delayed nerve regeneration of Col6a1–/– mice is induced by macrophage deficits and rejuvenated by transplantation of wild-type bone marrow cells. These results identify collagen VI as a novel regulator for peripheral nerve regeneration by modulating macrophage function. In the last year of my PhD I moved my focus to skin homeostasis and investigated the role of collagen VI in wound-induced hair regrowth. The data shows that collagen VI is strongly deposited in hair follicles, and it is dramatically upregulated by skin wounding. Lack of collagen VI in Col6a1–/– mice promotes wound-induced hair regrowth, but does not affect skin regeneration. Conversely, addition of purified collagen VI rescues the abnormal wound-induced hair regrowth in Col6a1–/– mice. Mechanistic studies revealed that the increased wound-induced hair regrowth of Col6a1–/– mice is triggered by upregulation of Keratin 79 and activation of the Wnt/beta-catenin signaling pathway, and is abolished by inhibition of the Wnt/beta-catenin pathway. These findings highlight the essential relationships between ECM and hair follicle regeneration, and point at collagen VI as a potential therapeutic target for hair loss. Altogether, the data I obtained during my PhD studies strongly support a key role of collagen VI in peripheral nerves and wound-induced hair follicle growth, thus paving the way for future studies on ECM molecules in PNS and skin under physiological and pathological conditions.