Roles of Mesenchymal Stem Cells in Tissue Regeneration and Immunomodulation

Abstract

Mesenchymal stem cells are classified as multipotent stem cells, due to their capability to transdifferentiate into various lineages that develop from mesoderm. Their popular appeal as cell-based therapy was initially based on the idea of their ability to restore tissue because of their differentiation potential in vitro; however, the lack of evidence of their differentiation to target cells in vivo led researchers to focus on their secreted trophic factors and their role as potential powerhouses on regulation of factors under different immunological environments and recover homeostasis. To date there are more than 800 clinical trials on humans related to MSCs as therapy, not to mention that in animals is actively being applied as therapeutic resource, though it has not been officially approved as one. But just as how results from clinical trials are important, so is to reveal the biological mechanisms involved on how these cells exert their healing properties to further enhance the application of MSCs on potential patients. In this review, we describe characteristics of MSCs, evaluate their benefits as tissue regenerative therapy and combination therapy, as well as their immunological properties, activation of MSCs that dictate their secreted factors, interactions with other immune cells, such as T cells and possible mechanisms and pathways involved in these interactions.

Keywords: Immunomodulation; Mesenchymal stem cells; Prostaglandin E2; Regenerative medicine; T regulators; Toll-like receptor.

Fig. 1.

MSC sources and secretome. MSC can be isolated from a variety of tissues, such as bone marrow, adipose tissue, placenta, umbilical cord, umbilical cord blood, liver, dental and more. MSC can transdifferentiate in vitro to other tissues but it is assumed that most of the benefits come from the factors they secret in the target environment.

Fig. 2.

MSC Activation. After there is tissue damage, different proinflammatory cytokines produced by lymphocytes can “activate” MSC to start producing anti-inflammatory factors like indoleamine 2,3-dioxygenase, prostaglandin E2, nitric oxide, interleukin 10. Pathogen-associated molecular patterns (PAMPS) and Damage-associated molecular patterns (DAMPS) can also activate MSC by ligating with toll-like-receptors on the surface of MSC. Depending on species, different TLR ligation can commit MSC to express either a pro-inflammatory phenotype (MSC1) which secretes proinflammatory cytokines like interleukin 6, interleukin-8, transforming growth factor beta, or an anti-inflammatory phenotype (MSC2).

Fig. 3.

Role of PEG2 and NO produced by MSC for immunosuppression. As MSCs are activated, they secrete various factors, among them, the anti-inflammatory prostaglandin E2. Depending on the environment, secretion levels of PEG2 will vary. If found in high levels, it can inhibit lymphocyte proliferation by reducing interleukin-2. In low levels, it can change Th1 to Th2 by blocking pro-inflammatory cytokines and it can also help induce T regs. At the same time, T regs can induce IDO secretion of MSC, and this works in synergy by helping T regs to produce the anti-inflammatory IL-10. Nitric Oxide can also produce an inhibition of T cell proliferation by inducing cell cycle arrest or apoptosis.