Abstract
Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Mechanical stimulations affect cell proliferation, differentiation, and migration, as well as determining tissue homeostasis and repair. By using a specially designed skin-stretching device, we discover that hair stem cells proliferate in response to stretch and hair regeneration occurs only when applying proper strain for an appropriate duration. A counterbalance between WNT and BMP-2 and the subsequent two-step mechanism are identified through molecular and genetic analyses. Macrophages are first recruited by chemokines produced by stretch and polarized to M2 phenotype. Growth factors such as HGF and IGF-1, released by M2 macrophages, then activate stem cells and facilitate hair regeneration. A hierarchical control system is revealed, from mechanical and chemical signals to cell behaviors and tissue responses, elucidating avenues of regenerative medicine and disease control by demonstrating the potential to manipulate cellular processes through simple mechanical stimulation.
Highlights
Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment
Most have focused on single cell population, such as keratinocytes, fibroblasts, or bone cells[34,35,36]; much less is known regarding the system complexity of living organism composed of multicell population
Some studies have attempted to mimic the in vivo state by coculturing keratinocytes and fibroblasts[37,38], these systems are still far from representing a physiological condition, because the existence of skin appendages is neglected and the inflammation process is prohibited without a vascular system
Summary
Tissues and cells in organism are continuously exposed to complex mechanical cues from the environment. Research has confirmed that arrector pili muscles, which connect the bulge region of a hair follicle (where the hair stem cells reside) to the basement membrane and perform the functions for goosebumps formation and hair follicle alignment through muscle contracture, are involved in the hair regeneration cycle[9,10,11] These phenomena prompted our interest in whether and how mechanical force influences stem cell behavior in vivo. Combined with the results of molecular analyses, as well as genetic and pharmacological manipulation, we discover that stretch stimulates chemokine production and macrophage recruitment These macrophages undergo M2 polarization and produce various growth factors such as hepatocyte growth factor (HGF) and insulin-like growth factor 1 (IGF-1) to induce hair regeneration
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