Mesenchymal Stromal Cells as Critical Contributors to Tissue Regeneration

Abstract

Adult stem cells that are tightly regulated by the specific microenvironment, or the stem cell niche, function to maintain tissue homeostasis and regeneration after damage. This demands the existence of specific niche components that can preserve the stem cell pool in injured tissues and restore the microenvironment for their subsequent appropriate functioning. This role may belong to mesenchymal stromal cells (MSCs) due to their resistance to damage signals and potency to be specifically activated in response to tissue injury and promote regeneration by different mechanisms. Increased amount of data indicate that activated MSCs are able to produce factors such as extracellular matrix components, growth factors, extracellular vesicles and organelles, which transiently substitute the regulatory signals from missing niche cells and restrict the injury-induced responses of them. MSCs may recruit functional cells into a niche or differentiate into missing cell components to endow a niche with ability to regulate stem cell fates. They may also promote the dedifferentiation of committed cells to re-establish a pool of functional stem cells after injury. Accumulated evidence indicates the therapeutic promise of MSCs for stimulating tissue regeneration, but the benefits of administered MSCs demonstrated in many injury models are less than expected in clinical studies. This emphasizes the importance of considering the mechanisms of endogenous MSC functioning for the development of effective approaches to their pharmacological activation or mimicking their effects. To achieve this goal, we integrate the current ideas on the contribution of MSCs in restoring the stem cell niches after damage and thereby tissue regeneration.

Keywords: adult stem cells; aging; mesenchymal stromal cells (MSC); regenerative medicine; stem cell niche.

Figure 1

Mechanisms of MSC participation in tissue regeneration. MSCs are able to differentiate into some niche components, as well as attract functional cells to a niche. MSCs are able to replenish the stem cell pool by endowing differentiated cells with stemness. A significant contribution of MSCs to tissue regeneration can be achieved due to their prevalence in tissues and the ability to respond to metabolic, mechanical, biological paracrine stimuli of the microenvironment with high plasticity. MSCs, mesenchymal stromal cells; ECM, extracellular matrix.

Figure 2

Functions of ECM components secreted by MSCs. ECM is a three-dimensional structure consisting of collagen, fibronectin, elastin, glycosaminoglycans, and various glycosylated proteins that are capable of transmitting mechanical and biochemical cues to cells. ECM stiffness can regulate the behavior of niche cells. The ability of the ECM to transmit biochemical signals is also due to its ability to deposit regulatory molecules and matrix-bounded vesicles, protecting them from degradation and localizing their effects.

Figure 3

MSC can regulate tissue regeneration by secretion of paracrine factors, extracellular vesicles, and organelle transfer. MSCs have the ability to respond to damage by changing the number and panel of secreted factors. Particularly, MSCs can exhibit a paracrine response to stem cell demand signals during damage and contribute to tissue regeneration. Another important response of MSCs to damage is the activation of an immunosuppression program. In addition to the secretion of individual paracrine factors, MSCs can secrete EV or transfer individual organelles, such as mitochondria, through vesicular or tunnel nanotube transport. MSCs, mesenchymal stromal cells; EV, extracellular vesicles.