Extrinsic regulation of hematopoietic stem cells in development, homeostasis and diseases

Abstract

Lifelong generation of blood and immune cells depends on hematopoietic stem cells (HSCs). Their function is precisely regulated by complex molecular networks that integrate and respond to ever changing physiological demands of the body. Over the past several years, significant advances have been made in understanding the extrinsic regulation of HSCs during development and in homeostasis. Propelled by technical advances in the field, the cellular and molecular components of the microenvironment that support HSCs in vivo are emerging. In addition, the interaction of HSCs with their niches is appreciated as a critical contributor to the pathogenesis of a number of hematologic disorders. Here, we review these advances in detail and highlight the extrinsic regulation of HSCs in the context of development, homeostasis, and diseases. WIREs Dev Biol 2017, 6:e279. doi: 10.1002/wdev.279 For further resources related to this article, please visit the WIREs website.

Figure 1. Extrinsic regulation of HSCs during ontogeny

A. An illustration depicting hematopoietic organs in mouse embryos. B. Timing and location of hematopoiesis during development. Hematopoiesis takes place in several anatomical sites. Primitive hematopoietic progenitors are found in the blood island of the yolk sac. AGM is the predominant site of HSC emergence although the placenta may also play a key role. HSCs migrate to, mature and expand in the fetal liver. Subsequently, HSCs transiently seed the fetal spleen and around birth, migrate to the bone marrow where HSCs reside throughout adult life. Under stress conditions, HSCs can egress from the bone marrow and take residence in the liver and spleen to initiate EMH. C. Candidate cellular components and extrinsic signals that regulate hematopoiesis during development. AGM, aorta-gonad-mesonephros; EMH, extramedullary hematopoiesis; EMT, epithelial-mesenchymal transition.

Figure 2. Homeostatic HSC extrinsic regulation

A. Anatomy of a mammalian long bone, the major hematopoietic organ in adults. B. In the bone marrow, HSCs are regulated by a variety of cell types including endothelial cells, heterogeneous populations of mesenchymal stromal cells, non-myelinating Schwann cells, megakaryocytes, macrophages and osteoblasts. Signals from sympathetic nerves, circulating factors and possibly hypoxia (not pictured) are also important. Key locally synthesized factors for HSC maintenance include SCF, CXCL12, TGF-β1 and CXCL4. C and D. Major and other HSC regulatory cells in the bone marrow, where major regulatory cells are required to maintain the HSC pool, and other regulatory cells affect the cell cycle, localization and downstream progeny of HSCs through direct and indirect mechanisms.

Figure 3. Disruption of extrinsic regulation of hematopoiesis

A. The aged hematopoietic niche (left) features increased adipogenesis, decreased osteogenesis, decreased vascularity, decreased numbers of mesenchymal stromal cells (MSCs), and decreased niche signaling factors. HSCs are less functional. In states of malignancy (right), extrinsic regulation can be disrupted in many different ways. I) Aberrant niche cells can incite malignancy and leukemia-initiating cells (LIC). II) Malignant cells can inhibit normal functioning of niche cells and reduce normal niche signaling as well as induce leukemia-reinforcing phenotypes in niche cells. III) Normal niche cells can inhibit disease progression. B. Dysregulation of the niche varies across different of abnormal conditions – old age, malignancy, inflammation and irradiation. Common themes emerge, including the loss of cell types promoting critical niche signaling factors, pointing to the importance of these pathways in maintaining hematopoiesis.