Mesenchymal Stem Cells Adaptively Respond to Environmental Cues Thereby Improving Granulation Tissue Formation and Wound Healing

Abstract

Granulation tissue formation constitutes a key step during wound healing of the skin and other organs. Granulation tissue concomitantly initiates regenerative M2 macrophages polarization, fibroblast proliferation, myofibroblast differentiation with subsequent contraction of the wound, new vessel formation, and matrix deposition. Impaired granulation tissue formation either leads to delayed wound healing or excessive scar formation, conditions with high morbidity and mortality. Accumulating evidence has demonstrated that mesenchymal stem cell (MSC)-based therapy is a promising strategy to ameliorate defects in granulation tissue formation and to successfully treat non-healing chronic wounds. In this review we give an updated overview of how therapeutically administered MSCs ensure a balanced granulation tissue formation, and furthermore discuss the cellular and molecular mechanisms underlying the adaptive responses of MSCs to cue in their direct neighborhood. Improved understanding of the interplay between the exogenous MSCs and their niche in granulation tissue will foster the development of MSC-based therapies tailored for difficult-to-treat non-healing wounds.

Keywords: environment sensing; granulation tissue; inflammation; mesenchymal stem cells; myofibroblasts; proliferation; scarring; wound healing.

FIGURE 1

Functional roles of MSCs in regulating granulation tissue formation. MSCs promote fibroblast proliferation and myofibroblast differentiation in a hypoproliferative environment, whereas they suppress myofibroblast activation and reduce myofibroblast numbers in a fibrotic environment. MSCs induce M1 to M2 transition and inhibit neutrophil activation in an over-inflamed environment, whereas they support cytotoxic T lymphocytes (CTL) and neutrophils for the clearance of infectious agents. Due to space limitation only selected examples of how MSCs impact on granulation tissue are depicted.

FIGURE 2

Cellular and molecular mechanisms underlying adaptive responses of MSCs. MSCs utilize rheostatic (sensing) mechanisms to respond to the local environment in granulation tissue with deficient or excessive trophic factors, inflammatory mediators, oxidative stress or mechanical stress. This adaptive response to cues from the microenvironment depends on distinct intracellular signaling, changes of the transcriptome and metabolic reprogramming. Adaptive MSC responses, in consequence, rebalance the partly hostile microenvironment, and thus protect themselves by rebalancing their niche, and this favors a shift to healing and tissue homeostasis. For further details see main text. CDH, cadherins; ITG, integrins; OXPHOS, oxidative phosphorylation, ROS, reactive oxygen species.