The biochemistry of hematopoietic stem cell development

Abstract

Background The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intra-embryonic microenvironments, most notably from ‘hemogenic’ endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. Scope of the review The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. Major conclusions The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo is overlapping, but differs significantly from the regulation of HSCs in the adult. General significance HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC generation in the developing embryo provides important new knowledge on how these complex stem cells are made, sustained and expanded in the embryo to give rise to the complete adult hematopoietic system, thus stimulating novel strategies for producing increased numbers of clinically useful HSCs.

Endothelial Smad4 restrains the transition to hematopoietic progenitors via suppression of ERK activation

“…2,3,42 Currently, increasing studies have disclosed the molecular identities of the niche for regulating AGM hematopoiesis by affecting multiple cellular behaviors of hematopoietic cells. 14,32,34,43 Most recently, the migration of the lateral plate mesoderm to the midline has been proven to be required for endothelial Runx1 expression to initiate aortic hematopoietic cluster generation in chick embryos.…”

“…4,7,9 It is proposed that definitive hematopoietic progenitors and HSCs are generated from distinct types of hemogenic endothelium, implying that distinct molecular programming is involved; these mechanisms are as yet poorly defined. [1][2][3]10 Of note, only a very small proportion of aortic endothelium has bloodforming capacity. In theory, physiological mechanisms restraining excessive endothelial-hematopoietic transition must exist, but remain largely unknown.…”

“…[1][2][3] Accumulating evidence from multiple research strategies has pinpointed that definitive hematopoietic progenitors and HSCs are directly formed from hemogenic endothelium, a unique type of structural endothelium with transient hematopoietic potential. [4][5][6][7][8] This process is, therefore, acknowledged as the endothelialhematopoietic transition, manifested intra-embryonically as the appearance of vascular hematopoietic clusters in the aorta, vitelline, and umbilical arteries.…”

ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver

“…3,4 At E15.5, these HSCs are released into the circulating blood and begin to home to the bone marrow. 5 Of note, the number of HSCs increases drastically from 2 to 3 to 800 to 1000 in mouse FL, 4 suggesting a unique and powerful effect of the FL microenvironment on the expansion of HSCs. Therefore, identifying novel regulators and microenvironment cues for HSC development in FL is of great importance.…”

Inflammatory signaling regulates hematopoietic stem and progenitor cell emergence in vertebrates

“…In vertebrate embryos, the earliest definitive hematopoietic stem and progenitor cells (HSPCs) are originated from a group of specialized endothelial cells, hemogenic endothelium (HE), [1][2][3][4] through the endothelial-to-hematopoietic transition (EHT) process. [5][6][7] In vitro generation and/or expansion of functional and transplantable bona fide HSCs with self-renewal and multilineage potential hold great promise in regenerative medicine.…”