Hematopoietic stem cell niche
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Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC).[1] As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis.[2] This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors.[2] This stem-cell niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.[2] Recent study marks the first global discovery of hematopoietic stem cell (HSC) niches within invertebrate skeletons—overturning the long-held belief that skeletal hematopoiesis is unique to vertebrates, offering a novel evolutionary perspective on stem cell biology.[3]
Hematopoiesis involves a series of differentiation steps from one progenitor cell to a more committed cell type, forming the recognizable tree seen in the adjacent diagram. Pluripotent long-term (LT)-HSCs self-renew to maintain the HSC pool, as well as differentiate into short-term (ST)-HSCs.[2] Through various knock-out models, several transcription factors have been found to be essential in this differentiation, such as RUNX1 and TAL1 (also known as SCL).[4][5]
ST-HSCs can then differentiate into either the common myeloid progenitor (CMP) or the common lymphoid progenitor (CLP). The CLP then goes on to differentiate into more committed lymphoid precursor cells. The CMP can then further differentiate into the megakaryocyte–erythroid progenitor cell (MEP), which goes on to make RBCs and platelets, or the granulocyte/macrophage progenitor (GMP), which gives rise to the granulocytes of the innate immune response. MEP differentiation was found to be contingent upon the transcription factor GATA1, whereas GMP differentiation needs SPI1. When expression of either was inhibited by morpholino in zebrafish, the other lineage programming pathway resulted.[6][7]
There are 2 types of hematopoiesis that occur in humans:
- Primitive hematopoiesis – blood stem cells differentiate into only a few specialized blood lineages (typically isolated to early fetal development).
- Definitive hematopoiesis – multipotent HSCs appear (occurs through the majority of human lifetime).
Historical development of the theory
The pioneering work of Till and McCulloch in 1961 experimentally confirmed the development of blood cells from a single precursor hematopoietic stem cell (HSC), creating the framework for the field of hematopoiesis to be studied over the following decades.[8] In 1978, after observing that the prototypical colony-forming stem cells were less capable at replacing differentiated cells than bone marrow cells injected into irradiated animals, Schofield proposed that a specialized environment in the bone marrow allows these precursor cells to maintain their cellular reconstitution potential.[9]
During this time, the field exploded with studies aimed at determining the components of the "hematopoietic stem cell niche" that made this possible. Dexter observed that mesenchymal stromal cells could maintain early HSCs ex vivo, and both Lord and Gong showed that these cells localized to the endosteal margins in long bones.[10][11][12] These studies and others[13] supported the idea that bone cells create the HSC niche, and all the research that elucidated this specialized hematopoietic microenvironment stemmed from these landmark studies.
Niche localization through early fetal development
Yolk sac and the hemangioblast theory
Despite the vast work done in this field, there is still controversy over the origins of definitive HSCs. Primitive hematopoiesis is first found in the blood islands (Pander's islands) of the yolk sac at E7.5 (embryonic day 7.5) in mice and 30dpc (30 days post-conception) in humans. As the embryo requires rapid oxygenation due to its high mitotic activity, these islands are the main source of red blood cell (RBC) production via fusing endothelial cells (ECs) with the developing embryonic circulation.
The hemangioblast theory, which posits that the RBCs and ECs derive from a common progenitor cell, was developed as researchers observed that receptor knockout mice, such as Flk1-/-, exhibited defective RBC formation and vessel growth.[14] A year later, Choi showed that blast cells derived from embryonic stem (ES) cells displayed common gene expression of both hematopoietic and endothelial precursors.[15] However, Ueno and Weissman provided the earliest contradiction to the hemangioblast theory when they saw that distinct ES cells mixed into a blastocyst resulted in more than 1 ES cell contributing to the majority of the blood islands found in the resultant embryo.[16] Other studies done in zebrafish have more soundly indicated the existence of the hemangioblast.[17][18][19] While the hemangioblast theory appears to be generally supported, most of the studies done have been in vitro, indicating a need for in vivo studies to elucidate its existence.[20]
Aorta-gonad-mesonephros region
Definitive hematopoiesis then occurs later in the aorta-gonad-mesonephros (AGM), a region of embryonic mesoderm that develops into the ventral wall of the dorsal aorta, at E10.5 in mice and 4wpc (4 weeks post-conception) in humans.[21] New HSCs either enter the aortic circulation or remain within the endothelium. While Notch 1 has been found to stimulate aortic HSC production, Runx1 overexpression in the zebrafish mutant mindbomb that lacks Notch signaling rescues HSC production, suggesting Runx1 is downstream of Notch1.[22][23] Hedgehog signaling is also required for HSC production in the AGM.[24] ECs located in this niche have been found to support new HSCs through the upregulation of factors such as p57 and IGF2.[25] The relocalization of hemogenic endothelium coincides with the migration of distinct endothelial precursors to the AGM.[26]
Niche relocation through late fetal development
Placenta and the fetal liver
Hematopoiesis then moves from the AGM to the placenta and fetal liver at E11.5 in mice and 5wpc in humans. While the engraftment of HSCs at these sites are still being elucidated, the interaction between the chemokine CXCL12 expressed by stromal cells and its receptor CXCR4 expressed on HSCs has been proposed as one mechanism.[27][28] In addition, the cytokine-receptor binding of SCF and KIT have been recognized for its importance in HSC function and amplification of the chemotactic induction of CXCL12.[29][30]
Additional factors that are important in HSC migration during this period are Integrins, N-cadherin, and Osteopontin that can stimulate Wnt signaling in HSCs.[31][32] Transcription factors such as PITX2 must be expressed in stromal cells to support normal HSC function.[33] Like with the AGM, the relocation of fetal liver HSCs coincides with the differentiation of functional units, in this case hepatoblasts to hepatocytes.[34] Mice have also shown hematopoietic activity in the umbilical arteries and the allantois, in which HSCs and endothelial cells are colocalized.[35]
Bone marrow
Hematopoiesis then moves to the bone marrow at E18 in mice and 12wpc in humans, where it will reside permanently for the remainder of the individual's lifetime. In mice, there is a shift from the fetal liver to the spleen at E14, where it persists for many weeks postnatally while it occurs simultaneously in the bone marrow.[36] This relocalization is thought to be supported by the development of osteoblast and chondrocyte precursor cells capable of forming an HSC niche.[37][38] In addition to the previously mentioned signals that induce HSC migration, TIE2-angiopoietin and CD44-E-cadherin binding appears to be important for this event to occur, as well as for the retention of these HSCs once they are in the bone marrow.[39][40]
HSCs in the bone marrow do not show the same characteristics as those in other niches. HSCs in fetal liver display increased cell divisions, whereas adult bone marrow HSCs are mostly quiescent.[20] This difference stems, in part, from signaling discrepancies in the two niches. Sox17 has been identified as crucial for the generation of fetal, but not adult, HSCs.[41] Inactivation of Runx1 in adult HSCs does not impair function, but rather prevents the differentiation of specific lineages.[42] Differences such as these in the reactivity of HSCs from different niches suggests that the signaling found there is not the same.
