Agrin-Matrix Metalloproteinase-12 axis confers a mechanically competent microenvironment in skin wound healing

Sayan Chakraborty (), Divyaleka Sampath, Melissa Ong Yu Lin, Matthew Bilton, Cheng-Kuang Huang, Mui Hoon Nai, Kizito Njah, Pierre-Alexis Goy, Cheng-Chun Wang, Ernesto Guccione, Chwee-Teck Lim and Wanjin Hong ()
Additional contact information
Sayan Chakraborty: Agency for Science, Technology, and Research (A*STAR)
Divyaleka Sampath: Agency for Science, Technology, and Research (A*STAR)
Melissa Ong Yu Lin: Agency for Science, Technology, and Research (A*STAR)
Matthew Bilton: National University of Singapore
Cheng-Kuang Huang: National University of Singapore
Mui Hoon Nai: National University of Singapore
Kizito Njah: Agency for Science, Technology, and Research (A*STAR)
Pierre-Alexis Goy: Agency for Science, Technology, and Research (A*STAR)
Cheng-Chun Wang: Agency for Science, Technology, and Research (A*STAR)
Ernesto Guccione: Agency for Science, Technology, and Research (A*STAR)
Chwee-Teck Lim: National University of Singapore
Wanjin Hong: Agency for Science, Technology, and Research (A*STAR)

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract An orchestrated wound healing program drives skin repair via collective epidermal cell proliferation and migration. However, the molecular determinants of the tissue microenvironment supporting wound healing remain poorly understood. Herein we discover that proteoglycan Agrin is enriched within the early wound-microenvironment and is indispensable for efficient healing. Agrin enhances the mechanoperception of keratinocytes by augmenting their stiffness, traction stress and fluidic velocity fields in retaliation to bulk substrate rigidity. Importantly, Agrin overhauls cytoskeletal architecture via enhancing actomyosin cables upon sensing geometric stress and force following an injury. Moreover, we identify Matrix Metalloproteinase-12 (MMP12) as a downstream effector of Agrin’s mechanoperception. We also reveal a promising potential of a recombinant Agrin fragment as a bio-additive material that assimilates optimal mechanobiological and pro-angiogenic parameters by engaging MMP12 in accelerated wound healing. Together, we propose that Agrin-MMP12 pathway integrates a broad range of mechanical stimuli to coordinate a competent skin wound healing niche.

Date: 2021
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DOI: 10.1038/s41467-021-26717-7

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