Cellular and molecular basis of haematopoiesis

Essentials: Haematopoiesis involves a regulated set of developmental stages by which haematopoietic stem cells (HSCs) produce haematopoietic progenitor cells which in turn differentiate into more mature haematopoietic lineages. These then provide all the key functions of the haematopoietic system. Development: Haematopoiesis occurs in distinct waves during development. Definitive HSCs first develop within the embryo in specialized regions of the dorsal aorta and umbilical arteries and then seed the fetal liver and bone marrow. HSC characteristics differ based on their site of development and age of the organism. Haematopoietic stem cells: At the single-cell level, these have the ability to reconstitute and maintain a functional haematopoietic system over extended periods of time in vivo. They (1) have a self-renewing capacity during the life of an organism, or even after transplantation; (2) are multipotent, with the ability to make all types of blood cells; and (3) are relatively quiescent, with the ability to serve as a deep reserve of cells to replenish short-lived, rapidly proliferating progenitors. In vivo transplantation models are currently the only reliable assays of HSC activity. Haematopoietic progenitor cells: These are unable to maintain long-term haematopoiesis in vivo due to limited or absent capacity for self-renewal. Their rapid proliferation and cytokine responsiveness enables increased blood cell production under conditions of stress. Lineage commitment means limited cell type production. The haematopoietic stem cell niche: An anatomically and functionally defined regulatory environment for stem cells modulates self-renewal, differentiation, and proliferative activity of stem cells, thereby regulating stem cell number. Niche function is important in maintaining haematopoietic integrity and niche dysfunction may contribute to haematopoietic disease. Niches for HSCs are dynamic, changing during development and with physiological stress. HSCs naturally traffic into and out of the niche, a feature that can be exploited for stem cell transplantation or harvesting, respectively. Bone marrow transplantation: Haematopoietic reconstitution during bone marrow transplantation is mediated by a succession of cells at various stages of development. More mature cells contribute to repopulation immediately following transplantation. With time, cells at progressively earlier stages of development are involved, with the final stable repopulation being provided by long-lived, multipotent HSCs. Long-term haematopoiesis is sustained by a relatively small number of HSCs.