Abstract: |
Hematopoietic stem cells (HSCs) are the most well-characterized tissue-specific stem cell. Over 50 years of basic research and clinical application has provided insight into the molecular and cellular mechanisms of HSC biology. HSC undergo self-renewal by symmetric or asymmetric division, or differentiation to common myeloid progenitors and progressively more differentiated myeloid and lymphoid progeny. The chemokine SDF-1/CXCL12 produced by marrow reticular cells plays a central role in regulating HSC migration and homing. HSC reside within a three-dimensional multicellular signaling unit or "niche" within the bone marrow. Within the niche HSC can be sustained in a dormant GO state. Accumulating genetic and functional data indicate molecular cross-talk between HSCs and osteoblasts, endothelial cells, and perivascular reticular cells that compose the endosteal and vascular niches. This involves large number of molecules (cytokines, chemokines, integrins, morphogens, and their receptors). The cytokines c-Kit ligand and thrombopoietin in particular are critical for HSC maintenance and self-renewal. The morphogens (Notch ligands, Wnt, Hedgehog, TGF beta, and BMP) also have variable and overlapping roles in supporting HSC self-renewal. Many of these secreted signaling molecules bind to the extracellular matrix and do not diffuse far or are presented by niche cells in transmembrane form (e.g., Jagged-Notch, Kit Ligand-c-Kit, Angiopoietin1-Tie2). Increased understanding of the molecular basis of HSC regulation will ultimately lead to protocols for maintenance and expansion of HSCs in vitro for clinical use in cell and gene therapies. |