Changes in tension regulates proliferation and migration of fibroblasts by remodeling expression of ECM proteins

Minmin Jiang; Juhui Qiu; Lingling Zhang; Dongyuan Lü; Mian Long; Li Chen; Xiangdong Luo

doi:10.3892/etm.2016.3497

Changes in tension regulates proliferation and migration of fibroblasts by remodeling expression of ECM proteins

Exp Ther Med. 2016 Sep;12(3):1542-1550. doi: 10.3892/etm.2016.3497. Epub 2016 Jul 1.

Authors

Minmin Jiang¹, Juhui Qiu², Lingling Zhang², Dongyuan Lü³, Mian Long³, Li Chen⁴, Xiangdong Luo²

Affiliations

¹ Burn Research Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Central Laboratory, The People's Hospital of Guizhou Province, Guiyang, Guizhou 550002, P.R. China.
² Burn Research Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; National Key Laboratory of Trauma and Burns and Chongqing Key Laboratory of Disease Proteomics, Chongqing 400038, P.R. China.
³ Key Laboratory of Microgravity (National Microgravity Laboratory) and Center for Biomechanics and Bioengineering, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, P.R. China.
⁴ Burn Research Institute, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; National Key Laboratory of Trauma and Burns and Chongqing Key Laboratory of Disease Proteomics, Chongqing 400038, P.R. China; Breast Disease Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.

Abstract

Wound healing is a complicated but highly organized process in which cell migration and proliferation are actively involved. However, the process by which mechanical stretch regulates the proliferation and migration of human skin fibroblasts (HFs) and keratinocytes is poorly understood. Using a house built mechanical stretch device, we examined the HFs extracellular matrix (ECM) components changes under non-stretch, static stretch or cyclic stretch conditions. We further investigated the changes in ECM component protein expression levels in keratinocytes and analyzed the effects of individual ECM component on keratinocyte proliferation and migration. Particularly, the roles of calcium/calmodulin-dependent serine protein kinase (CASK) in the HF proliferation under cyclic stretch were investigated. Cyclic stretch suppressed HF proliferation compared with HFs without stretch or with static stretch. Cyclic stretch also led to a significant reduction in the levels of collagen I and a marked increase of fibronectin in HFs ECM. By contrast, collagen I levels increased and fibronectin levels decreased in response to non-stretch and static stretch conditions. After cyclic stretch, the proliferation of keratinocytes was inhibited by the cyclic stretch-induced ECM in HFs. The inoculation of keratinocytes with single ECM component suggested that collagen I was more capable of inducing cell proliferation than fibronectin, while it had less impact on cell migration compared with fibronectin. Furthermore, cyclic stretch induced by proliferation inhibition was associated with altered integrin β1-CASK signal pathway. The present results demonstrated the existence of HF-ECM-keratinocyte 'cross-talk' in cutaneous tissues. Thus, the integrin β1-CASK signal pathway in HFs may be involved in the outside-in signal transduction of extracellular stretch and the altered ECM component expression.

Keywords: calcium/calmodulin-dependent serine protein kinase; extracellular matrix; human skin fibroblast; integrin; keratinocyte; mechanical stretch.