Immunobiology of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) can be isolated from almost all tissues and effectively expanded in vitro. Although their true in situ properties and biological functions remain to be elucidated, these in vitro expanded cells have been shown to possess potential to differentiate into specific cell lineages. It is speculated that MSCs in situ have important roles in tissue cellular homeostasis by replacing dead or dysfunctional cells. Recent studies have demonstrated that in vitro expanded MSCs of various origins have great capacity to modulate immune responses and change the progression of different inflammatory diseases. As tissue injuries are often accompanied by inflammation, inflammatory factors may provide cues to mobilize MSCs to tissue sites with damage. Before carrying out tissue repair functions, MSCs first prepare the microenvironment by modulating inflammatory processes and releasing various growth factors in response to the inflammation status. In this review, we focus on the crosstalk between MSCs and immune responses and their potential clinical applications, especially in inflammatory diseases.

Figure 1

The properties of MSCs. MSCs can be isolated from various tissues including adipose, bone marrow, umbilical cord, muscle and tooth root. After in vitro expansion, MSCs can be defined by several characteristics. Morphologically, MSCs are fibroblast like. They also express a panel of markers: positive for Sca-1, CD105, CD73, CD29 and CD90, and negative for CD31, CD34, CD45 and CD11b. In addition, MSCs have the potential to differentiate into adipocytes, chondrocytes, osteoblasts and other cell types

Figure 2

Tissue reparative properties of MSCs. Under the stimulation of different inflammatory cytokines at the damaged tissue sites, the newly immigrated MSCs release a plethora of growth factors, including EGF, FGF, PDGF, TGF-β, VEGF, HGF, Ang-1, KGF, SDF-1, IGF-1 and others. These growth factors orchestrate endothelial cells, fibroblasts as well as stem cells to promote tissue regeneration and repair through enhancing angiogenesis, inhibiting leukocyte transmigration and eliciting intrinsic progenitor cell/stem cell differentiation

Figure 3

Immunosuppressive properties of MSCs. Damaged tissues are always accompanied by infiltration of immune cells and MSCs. Inflammation triggers the production of high levels of chemokines and adhesion molecules in MSCs, including CXCR3 ligands, CCR5 ligands, ICAM-1 and VCAM-1. These molecules induce the accumulation of immune cells in close association with MSCs, whereby high concentrations of NO (in murine MSCs) or depletion of tryptophan (in human MSCs) leads to the inhibition of immune cells. Other immunosuppressive factors such as IL-10, TSG6, IL-6, LIF, PGE2, HO-1 and truncated CCL2 could also affect immune cell activation, proliferation and functions

Figure 4

A proposed model of the interaction between MSCs and immune responses during tissue repair. Once tissue injury occurs, MSCs are mobilized. Vigorous inflammation licenses MSCs to possess the abilities to downregulate immune responses, a process mediated by high levels of chemokines and immune inhibitory factors. In addition, growth factors are also released by MSCs, which promote endothelial cells and mesenchymal stem/stromal cells to repair injury. Insufficient inflammatory cytokines during chronic inflammatory sites, however, could stimulate MSCs to produce chemokines and tropic factors in absence of sufficient immune inhibitory factors. As such, chronic inflammation may lead MSCs to protract the disease recovery, or even worsen the disease course