Role of stem/progenitor cells in reparative disorders

Abstract

Adult stem cells are activated to proliferate and differentiate during normal tissue homeostasis as well as in disease states and injury. This activation is a vital component in the restoration of function to damaged tissue via either complete or partial regeneration. When regeneration does not fully occur, reparative processes involving an overproduction of stromal components ensure the continuity of tissue at the expense of its normal structure and function, resulting in a "reparative disorder". Adult stem cells from multiple organs have been identified as being involved in this process and their role in tissue repair is being investigated. Evidence for the participation of mesenchymal stromal cells (MSCs) in the tissue repair process across multiple tissues is overwhelming and their role in reparative disorders is clearly demonstrated, as is the involvement of a number of specific signaling pathways. Transforming growth factor beta, bone morphogenic protein and Wnt pathways interact to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells (TSCs), determining whether functional regeneration or the formation of scar tissue follows an injury. A growing understanding of both TSCs, MSCs and the complex cascade of signals regulating both cell populations have, therefore, emerged as potential therapeutic targets to treat reparative disorders. This review focuses on recent advances on the role of these cells in skeletal muscle, heart and lung tissues.

Figure 1

Potential sources of MSCs in tissue repair. During injury or disease tissue-resident MSCs (mesenchymal stromal/stem cells) can expand and provide trophic support for regeneration and/or differentiate to produce fibrosis, fatty degeneration or ectopic ossification or a combination of these. In addition, contribution to the fibrogenic cell pool by circulating “fibrocytes” originated from BM (bone marrow) and either EMT/EndMT (epithelial-mesenchymal transition/endothelial-mesenchymal transition) are proposed even though their existence, as well as the impact of their contribution to the deposition of fibrotic matrix, is controversial.

Figure 2

Fibro/adipogenic progenitors (FAPs) in skeletal muscle. Confocal image of a cluster of muscle fibers harvested from non-damaged muscle showing the relationship between mesenchymal progenitors expressing nuclear GFP under the control of the PDGFRα locus and fiber-associated blood vessels positive for CD31 (red). Nuclei are stained blue.

Figure 3

Signaling pathways driving mesenchymal stem cells to differentiate into lineages found in reparative disorders. While Wnt10b represses adipogenesis through the activity of B-catenin/TCF/Lef transcriptional complexes, activation of the non-canonical Wnt pathway by Wnt5b leads to repression of TCF/β-catenin transcriptional activity and yields the opposite results. Non-canonical TGFβ signaling participates in bone formation through activation of the osteogenesis regulator Runx2. On the other hand, canonical TGFβ signaling plays a central role in the regulation of the fibrogenic gene program. The BMP signaling pathway drives osteogenesis through SMADs 1, 5, 8 and shares the SMAD4 component with the TGFβ pathway.