The life and fate of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSC) are present throughout the body and are thought to play a role in tissue regeneration and control of inflammation. MSC can be easily expanded in vitro and their potential as a therapeutic option for degenerative and inflammatory disease is therefore intensively investigated. Whilst it was initially thought that MSC would replace dysfunctional cells and migrate to sites of injury to interact with inflammatory cells, experimental evidence indicates that the majority of administered MSC get trapped in capillary networks and have a short life span. In this review, we discuss current knowledge on the migratory properties of endogenous and exogenous MSC and confer on how culture-induced modifications of MSC may affect these properties. Finally, we will discuss how, despite their limited survival, administered MSC can bring about their therapeutic effects.

Keywords: culture; homing; mesenchymal stem cells; migration; survival.

Figure 1

Two potential routes for recruitment of endogenous MSC after tissue injury. (A) Cytokines, chemokines, and growth factors like SCF, G-CSF, and SDF-1 are released by the injured tissue, which may trigger recruitment of MSC from the bone marrow to sites of injury via the circulation. (B) Alternatively, MSC are recruited from within tissues to sites of injury via migration within the stroma or via micro-capillaries. SCF, stem cell factor; G-CSF, granulocyte-colony stimulating factor; SDF-1, stromal cell derived factor-1; BM, bone marrow.

Figure 2

Proposed mechanism of action of intravenously injected cultured MSC. Administered culture-expanded MSC (large violet cells) target immune cells, including macrophages, and resident progenitor cells, including MSC (small red cells) via their secretome (e.g., TGF-β, PGE-2, and other factors) to stimulate immunomodulatory and regenerative processes. In addition, phagocytosis of MSC by macrophages may induce the formation of regulatory macrophages. TGF-β, transforming growth factor-β; PGE-2, prostaglandin E2.

Figure 3

Proposed model of MSC contribution to immune suppression and tissue repair. Intravenous administration of culture-expanded MSC (violet cells) leads to modulation of the function of endogenous MSC (red cells) and macrophages via the secretome of the administered cells (e.g., TGF-β, PGE-2, and other factors) and phagocytosis of MSC by macrophages. The activation of resident MSC and induction of regulatory macrophages induces tissue regeneration. MSC furthermore induce regulatory T cells via different mechanisms, including the secretion of TGF-β and an indirect elevation of IL2. Administration of MSC also elicits a systemic immune response, which triggers an immunosuppressive response.