Emerging roles for multipotent, bone marrow-derived stromal cells in host defense

Abstract

Multipotent, bone marrow-derived stromal cells (BMSCs, also known as mesenchymal stem cells [MSCs]), are culture-expanded, nonhematopoietic cells with immunomodulatory effects currently being investigated as novel cellular therapy to prevent and to treat clinical disease associated with aberrant immune response. Emerging preclinical studies suggest that BMSCs may protect against infectious challenge either by direct effects on the pathogen or through indirect effects on the host. BMSCs may reduce pathogen burden by inhibiting growth through soluble factors or by enhancing immune cell antimicrobial function. In the host, BMSCs may attenuate pro-inflammatory cytokine and chemokine induction, reduce pro-inflammatory cell migration into sites of injury and infection, and induce immunoregulatory soluble and cellular factors to preserve organ function. These preclinical studies provide provocative hints into the direction MSC therapeutics may take in the future. Notably, BMSCs appear to function as a critical fulcrum, providing balance by promoting pathogen clearance during the initial inflammatory response while suppressing inflammation to preserve host integrity and facilitate tissue repair. Such exquisite balance in BMSC function appears intrinsically linked to Toll-like receptor signaling and immune crosstalk.

Figure 1

MSCs down-modulate in vitro pro-inflammatory responses. Using in vitro assays, BMSCs have been shown to interact with immune effector cells either through direct contact or through the induction of paracrine immunomodulatory soluble factors, such as galectin-1, HO-1, HLA-G5, hepatocyte growth factor, IL-10, IDO, PGE₂, and TGF-β1. Specifically, BMSCs inhibit monocyte (Mo) differentiation into DCs as well as DC activation and maturation; inhibit naive T-cell activation, Th1 proliferation, and cytokine production (TNF-α and IFN-γ); inhibit B-cell proliferation and differentiation into plasma cells; and inhibit NK cell proliferation, cytotoxicity, and IFN-γ production. In contrast, BMSCs induce Treg cells. Soluble factors, including IL-1β, IFN-γ, TNF-α, and TLR ligands, have been shown to provide necessary signals for in vitro MSC activation.

Figure 2

Signals mediating in vivo BMSC activation in the context of infectious challenge and their subsequent effects on MSC-mediated immunomodulation remain largely undefined. Infectious challenge is associated with induction in pathogen- and sterile-induced soluble factors that may influence BMSC activation and subsequent immunomodulation. As infectious burden increases, so too do associated inflammatory and damage burdens at the site of infection. By nature of their multipotency, BMSCs may possess plasticity in their immunomodulatory effects to respond to the changing microenvironment at the site of infectious challenge. Specifically, the inflammatory and damage milieu may instruct or “license” BMSC activation and function specific to the microenvironment in which BMSCs reside or to which they migrate as a consequence of infection. Further investigation is needed to define these signals within the in vivo microenvironment as well as their effects on MSC activation in addition to resultant immunomodulatory effects of MSCs on host immunity.

Figure 3

The host immune response to infectious challenge affords multiple potential signals for BMSC activation. TLRs recognize PAMPs and DAMPs within the microenvironment. The microenvironment milieu is the composite of resident and immigrating hematopoietic and nonhematopoietic cells responding to pathogen and the associated constitutive and inducible soluble factors that these cells produce. During infectious challenge, TLR ligands activate immune effector cells, such as DCs, monocytes, and macrophages (Mo/Mφ), and T cells to produce pro-inflammatory cytokines and chemokines. These soluble factors in turn activate additional host defense responses, including recruitment of immune effector cells (chemotaxis gradient). Pathogen is eliminated directly through immune effector cells themselves (eg, phagocytosis) and by the antimicrobial soluble factors they produce (eg, TNF-α and IFN-γ). Resultant pathogen cell necrosis and tissue toxicity release additional DAMPs, which accumulate and form pro-inflammatory damage and oxygen stress gradients. To preserve host integrity, regulatory hematopoietic cells, also activated by PAMPs and DAMPs, function to counter inflammation through the production of anti-inflammatory and antioxidant paracrine soluble factors. BMSCs possess TLRs, which could potentially recognize pathogen and danger signals and activate BMSCs to function as nonhematopoietic immunomodulatory cells during infection. Block arrows (≫) indicate potential influences within each phase of host response to infection that may influence BMSC activation and function. Further investigation is needed to confirm these putative signals.

Figure 4

Proposed plasticity in BMSC response and function during infectious challenge. To decrease infectious burden (left white triangle), the host requires intact immunity (left black triangle). That is, level of pathogen burden in the host inversely correlates with host immune competency. BMSCs may act as pro-inflammatory agents in the initial stages of the host response to infectious challenge, thereby decreasing pathogen burden by augmenting antimicrobial immune responses. However, high-level, persistent systemic inflammation (right white triangle) ultimately results in decreased host survival (right black triangle). Therefore, BMSCs may assume an immunomodulatory function to dampen the pro-inflammatory response associated with host immune response to pathogen. In this regard, BMSCs might maintain immune homeostasis after infectious challenge, by preserving host integrity through mediating initial pro-inflammatory, antimicrobial effects and then shifting function to attenuate inflammation and to augment tissue repair.