Modulating the stem cell niche for tissue regeneration

Abstract

The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell-extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell-niche interactions.

Figure 1

Composition of the niche. Stem cell niches are complex, heterotypic, dynamic structures, which include different cellular components, secreted factors, immunological control, ECM, physical parameters and metabolic control. These aspects of the niche are described in more detail in Box 1. The interactions between stem cells and their niches are bidirectional and reciprocal.

Figure 2

Representative schema illustrating stem cell niches. (a–c) Discrete niches that support hematopoietic (a), epidermal (b) and intestinal stem cells (c). b adapted from ref. with permission from Elsevier; c adapted from ref. , Nature Publishing Group.

Figure 3

Manipulation of the hematopoietic stem cell niche in vivo. In vivo manipulation of HSCs may be achieved by altering constituent niche cells, by administering drugs to alter cellular localization, by disrupting adhesive interactions or by stabilization of nutritional support (e.g., promoting hypoxia). Immune regulation of the HSC niche may be targeted through immunosuppressive medications or in allogeneic transplantation. HSC mobilization is regulated in part by the HSC niche and can be achieved with cytokine growth factors or by blocking adhesion molecules.