Stromal Cell-Derived Factor 1 (SDF-1) Signaling and Tissue Homeostasis

Abstract

Stromal cell-derived factor 1 (SDF-1) or C-X-C motif chemokine 12 (CXCL12) is a highly potent chemoattractant and paracrine protein with critical roles in embryogenesis and hematopoiesis, as well as postnatal tissue repair and regeneration. It acts through the chemokine receptor 4 (CXCR4) and CXCR7 receptors to mediate chemotactic processes including cell signaling and the expression of adhesion molecules, proteinases, and angiogenic factors. During embryogenesis, embryonic stem cells expressing CXCR4 rely on SDF-1 gradients to guide their migration to their target tissues. In the postnatal period, SDF-1 is best known for governing the hematopoietic stem cell (HSCs) niche in the bone marrow (BM) and facilitating the engraftment of transplanted HSCs. More recently, its role in tissue repair has begun to be elucidated. Tissue injury and subsequent hypoxia leads to a hypoxia-inducible factor 1 (HIF-1) mediated increase in endothelial expression of SDF-1. The resultant intravascular SDF-1 gradient recruits hematopoietic lineage cells and lineage negative cells to the site of injury. Endothelial expression of SDF-1 also influences the behavior of tissue-resident cells, promoting proliferation and migration and potentiating paracrine activity. The various downstream effects of SDF-1 expression act in concert to promote neovascularization and tissue regeneration. Impaired regenerative capacity in the setting of aging and disease states such as diabetes is partly due to deficiencies in SDF-1 signaling. Conversely, the unregulated tissue generation of cancer appears to rely on overexpression of SDF-1. Understanding these pathways and their molecular regulation will inform the development of novel targeted therapies across the spectrum of tissue homeostasis.