Dynamic niches in the origination and differentiation of haematopoietic stem cells

Key Points Haematopoietic stem cells (HSCs) are maintained in specialized microenvironments known as 'niches', which are composed of complex cellular and acellular components. Recent advances have contributed significantly to our understanding of what the niche is and how it changes during development, ageing and disease. In particular, powerful new imaging techniques permit the direct observation of HSCs in their niches. These techniques provide novel insights concerning the emergence of HSCs from the dorsal aorta in fetal haematopoiesis, as well as the associations between HSCs and niche components in adult haematopoiesis. Previous conceptions of niches as static, anatomically-defined bone marrow microenvironments consisting predominantly of one cell type are being challenged. Increasingly, it is becoming clear that the niche is an anatomically fluid and very dynamic environment, wherein multiple physical and cellular inputs are integrated by HSCs. Physical inputs that are known to be important in haematopoiesis include oxygen tension, calcium concentration, shear force and mechanical support. Identified bone marrow niche cells include osteoblasts, vascular endothelial cells, mesenchymal stem cells, CXCL12-abundant reticular cells, neural cells and adipocytes. Recent work demonstrates that dysfunctional haematopoiesis, such as that seen in patients with myelodysplasia and leukaemia, can result from defects in the microenvironment alone, without genetic perturbation of HSCs. This indicates that strategies for correcting haematopoietic diseases that target only the HSC may be insufficient or incomplete. Many current clinical trials are exploiting our expanding knowledge of niche biology to improve haematopoietic stem cell transplantation. At present, such studies are largely restricted to targeting relevant niche pathways to effect HSC expansion ex vivo before transplantation; however, future clinical trials will be likely to allow more-directed manipulation of haematopoiesis in vivo . Haematopoietic stem cell function is tightly controlled to maintain haematopoietic homeostasis, in part by specialized cells and factors that constitute the haematopoietic 'niche'. Recent discoveries have engendered a new appreciation for the dynamic nature of the niche, identifying novel cellular and acellular niche components and uncovering fluctuations in their importance over time. Haematopoietic stem cells (HSCs) are multipotent, self-renewing progenitors that generate