Effect of the Microenvironment on Mesenchymal Stem Cell Paracrine Signaling: Opportunities to Engineer the Therapeutic Effect

Abstract

Cues from the extracellular environment, including physical stimuli, are well known to affect mesenchymal stem cell (MSC) properties in terms of proliferation and differentiation. Many therapeutic strategies are now targeting this knowledge to increase the efficacy of cell therapies, typically employed to repair tissue functions in the event of injury, either by direct engraftment into the target tissue or differentiation into mature tissues. However, it is now envisioned that harnessing the repertoire of factors secreted by MSCs (termed the secretome) may provide an alternate to these cell therapies. Of current interest are both direct protein secretions and two major subpopulations of bioactive extracellular vesicles (EVs), namely exosomes and microvesicles. EVs released by MSCs are reflective of their cells of origin, able to impact upon the activities of other cells in the local microenvironment, making the rational design of MSC paracrine activities an encouraging strategy to reproducibly modulate cell therapies. The precise mechanisms by which the secretome is modulated by the microenvironment, however, remain elusive. Controlling MSC growth conditions with oxygen tension, growth factor composition, and mechanical properties may serve to directly influence paracrine activity. Our growing understanding implicates components of the mechanotransduction machinery in translating both mechanical and chemical cues from the environment into alterations in gene regulation and varied paracrine activity. As technologies are developed to manufacture MSCs, advances in bioengineering and novel insight of how the extracellular environment affects MSC paracrine activity will play a pivotal role in the generation of widespread, successful, clinical MSC therapies.

Exosomes from human adipose‐derived stem cells promote proliferation and migration of skin fibroblasts

“…[9] This study demonstrates that the exosomes derived from ASCs play a prosurvival role in human dermal fibroblasts by stimulating its cell cycle and that microRNAs that are known to have regenerative potentials were enriched in ASC-exo. Our finding may be of useful for developing novel therapeutic methods for the enhancing wound healing.…”

The therapeutic potential of three-dimensional multipotent mesenchymal stromal cell spheroids

“…The changes in cell–matrix and cell–cell interactions lead to significant rearrangement of physical forces acting on each cell within the 3D spheroid, changing the polarization, cytoskeleton organization and morphology of cells. Substrate stiffness and elasticity significantly influence paracrine properties of MSCs [26, 27]. The differences in strain and rigidity that occurred during spheroid formation compared with standard tissue culture plastic were shown to be significant [26, 28].…”

A silk fibroin/decellularized extract of Wharton’s jelly hydrogel intended for cartilage tissue engineering

“…Mesenchymal stem cells (MSCs) are utilized as a common cell source in tissue engineering (Hao et al 2013; Sundaram et al 2017). The important characteristics of these cells such as survival, self-renewal, and differentiation highly depend on their surrounding extracellular matrix (ECM) (Hao et al 2013; Kusuma et al 2017). Therefore, one of the major challenges in this field is to provide a suitable biomaterial which is able to mimic the native niche of cells properly (Herrero-Mendez et al 2017).…”