Mechanical stretch induces hair regeneration through the alternative activation of macrophages

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.

Functional complexity of hair follicle stem cell niche and therapeutic targeting of niche dysfunction for hair regeneration

“…Additionally, macrophages also mediate the sensing of mechanical cues. Stretching skin can polarizes macrophages toward a M2 phenotype [92]. Pro-regenerative M2 macrophages stimulate hair regeneration via paracrine secretion of IGF and HGF.…”

MicroRNA-enriched small extracellular vesicles possess odonto-immunomodulatory properties for modulating the immune response of macrophages and promoting odontogenesis

“…Macrophages have essential modulatory functions in tissue regeneration [ 29 ]. Indeed, macrophage recruitment is enhanced in the early phase of pulp regeneration [ 30 ].…”

Alveolar cells under mechanical stressed niche: critical contributors to pulmonary fibrosis

“…M1 macrophages mainly function in the host defense system to eliminate pathogens by generating pro-inflammatory chemokines and cytokines such as TNF-α, CCL2 and ILs (Saradna et al 2018 ; Murray and Wynn 2011 ) whereas M2 harbors anti-inflammatory properties and engages in ECM remodeling (Mantovani et al 2004 ). Despite the chemical factors, emerging evidence suggests that physical environment contributes to the regulation of macrophage polarization (Fereol et al 2006 ; Pugin et al 1998 ; McWhorter et al 2015 ; Chu 2019 ; Shan 2019 ). As aforementioned, the PF lung exhibits a rigid condition by over deposition of ECM, thus it is reasonable to speculate the cross-talk between alveolar macrophages and the rigid alveolar environment.…”

“…Indeed Shan et al showed mechanical stress induces the mouse murine Mφ RAW264.7 cells polarize to M1 via the FAK/NF-κB signaling pathway (Shan 2019 ), considering the deletion of TLR-4 (the major pathway for M1 macrophage activation) manifested increased susceptibility to bleomycin induced lung fibrosis (Jiang et al 2005 ; Paun et al 2010 ). Nevertheless, another group reported that mechanical stress polarized macrophage to M2 phenotype in hair regeneration (Chu 2019 ). This discrepancy could be partially explained as previously reported, a moderate strain was shown to increase the ratio of M2/M1 macrophages over a 7-day period (McWhorter et al 2015 ),while a more extensive strain resulted in marked reduction in M2/M1 macrophages (Ballotta et al 2014 ).…”