Rethinking regeneration: empowerment of stem cells by inflammation

The ontogenetic development and maintenance of tissue homeostasis at the cellular level are accomplished by regulating the activation, renewal, expansion and differentiation of stem cells. The differentiation and regeneration potential of stem cells has been well studied in both preclinical and clinical investigations. 1 In recent years, a series of experiments have revealed that replacement of damaged or defective cells by exogenously administered stem cells is critical in achieving their therapeutic effects in various diseases, such as multiple sclerosis (MS). 2 However, modulation of experimental autoimmune encephalomyelitis (the animal model of MS) by neural progenitor cells (NPCs) has been found to be related to the immunoregulatory properties of these cells, and can be even achieved with irradiated NPCs or just NPC-derived supernatant, indicating that stem cell-based tissue repair can also be promoted by their immunoregulatory and paracrine effects. 3 More persuasive studies of stem cell-mediated immunoregulation have been carried out with mesenchymal stem/stromal cells (MSCs), multipotent cells that can be isolated from many tissues, such as bone marrow, adipose tissue and umbilical cord, which are capable of differentiation into adipocytes, osteoblasts, chondrocytes and myoblasts. 4 Interestingly, MSCs have been demonstrated to suppress an immune response through licensing by combinations of pro-inflammatory cytokines, specifically IFN γ in combination with TNF α or IL-1, leading to the concept of bidirectional interaction between MSCs and inflammation. 5 Under inflammatory conditions, ample amounts of growth factors produced by MSCs can facilitate tissue repair through their effects on endothelial cells and fibroblasts, as well as tissue progenitor cells, at sites of damaged tissue. Such concerted actions of MSCs on tissue repair have been termed as ‘cell empowerment’. 6 It is important to point out that most biological properties involved in the interplay between stem cells and immune responses are derived from studies with cells expanded ex vivo , rather than investigations exploring this interaction in vivo.