A general overview of vertebrate hematopoiesis
Blood development in vertebrates involves two waves of hematopoiesis: the primitive wave and the definitive wave (Galloway and Zon, 2003). The primitive wave, which involves an erythroid progenitor, gives rise to erythrocytes and macrophages during early embryonic development (Palis and Yoder, 2001). The
primary purpose of the primitive wave is to produce red blood cells that can facilitate tissue oxygenation as the embryo undergoes rapid growth (Orkin and Zon, 2008). In mammals and avians, these erythroid progenitor cells first appear in blood islands in the extra-embryonic yolk sac early in development (Paik and Zon, 2010). The primitive wave is transitory, however, and these erythroid progenitors are not pluripotent and do not have renewal capability. Definitive hematopoiesis, by contrast, occurs later in development, notably at different time points in different species. In most organisms, there is a transient wave of definitive hematopoiesis that occurs in the blood islands and produces progenitors called erythroid-myeloid progenitors (EMPs) (McGrath et al., 2011; Bertrand et al., 2007). Definitive hematopoiesis later involves HSCs, which are multipotent and can give rise to all blood lineages of the adult organism. In vertebrates, definitive HSCs are born in the aorta-gonad-mesonephros (AGM) region of the developing embryo. They migrate to the fetal liver and then to the bone marrow, which is the location for HSCs in adults (Cumano and Godin, 2007).
In humans, hematopoiesis begins in the yolk sac and transitions into the liver temporarily before finally establishing definitive hematopoiesis in the bone marrow and thymus. Experiments with human embryos confirm observations in the hemangioblast, a common precursor for endothelial and hematopoietic cells. In humans, HSCs are present in close proximity to endothelial cells (Tavian et al., 2010), and flow cytometry-sorted vascular endothelial cells from fetal and embryonic human blood-forming tissues cultured over a layer of MS-5 stromal cells underwent hematopoiesis (Tavian et al., 2010). These endothelial cells were sorted from the human embryonic aorta between day 27 and day 40 of development, which is when HSCs are present in this region. Studies using transplantation of HSCs from human embryos into immune-deficient mice have confirmed that the first definitive human HSCs are born in the AGM (Ivanovs et al., 2011). The embryonic origin of hematopoiesis in humans has been reviewed by Tavian et al. (Tavian et al., 2010).
The process of blood development in zebrafish is similar to that occurring in mammals, involving waves of hematopoiesis. During gastrulation, three germ layers are generated – ectoderm, mesoderm and endoderm – and these are then specified into different tissues. Mesoderm is specified into both a dorsal fate, in which somites and the notochord arise, and a ventral fate, in which blood, the vasculature and the pronephros arise. Primitive erythroid progenitors are born in the intermediate cell mass (ICM), which is a tissue derived from the ventral mesoderm (Detrich et al., 1995). The circulation of these primitive cells begins at ~24 hours post-fertilization (hpf). EMP progenitors arise from the posterior ICM region. During the definitive wave, HSCs emerge from the ventral wall of the dorsal aorta beginning at 30 hpf (Thompson et al., 1998; Burns et al., 2002; Kalev-Zylinska et al., 2002). These HSCs migrate to the caudal hematopoietic tissue (CHT) in the posterior region of the tail (Murayama et al., 2006; Jin et al., 2007). By 3 days post-fertilization (dpf), lymphopoiesis occurs in the thymus and one day later the HSCs migrate to the kidney marrow, which is analogous to the bone marrow in mammals.
Prior to birth, hemopoiesis occurs in a number of tissues, beginning with the yolk sac of the developing embryo, and continuing in the fetal liver, spleen, lymphatic tissue, and eventually the red bone marrow. Following birth, most hemopoiesis occurs in the red marrow, a connective tissue within the spaces of spongy (cancellous) bone tissue. In children, hemopoiesis can occur in the medullary cavity of long bones; in adults, the process is largely restricted to the cranial and pelvic bones, the vertebrae, the sternum, and the proximal epiphyses of the femur and humerus.
All formed elements arise from stem cells of the red bone marrow. Recall that stem cells undergo mitosis plus cytokinesis (cellular division) to give rise to new daughter cells: One of these remains a stem cell and the other differentiates into one of any number of diverse cell types. Stem cells may be viewed as occupying a hierarchal system, with some loss of the ability to diversify at each step. The totipotent stem cell is the zygote, or fertilized egg. The totipotent (toti- = “all”) stem cell gives rise to all cells of the human body. The next level is the pluripotent stem cell, which gives rise to multiple types of cells of the body and some of the supporting fetal membranes. Beneath this level, the mesenchymal cell is a stem cell that develops only into types of connective tissue, including fibrous connective tissue, bone, cartilage, and blood, but not epithelium, muscle, and nervous tissue. One step lower on the hierarchy of stem cells is the hemopoietic stem cell, or hemocytoblast. All of the formed elements of blood originate from this specific type of cell.
The lifespan of the formed elements is very brief. Although one type of leukocyte called memory cells can survive for years, most erythrocytes, leukocytes, and platelets normally live only a few hours to a few weeks. Thus, the body must form new blood cells and platelets quickly and continuously. When you donate a unit of blood during a blood drive (approximately 475 mL, or about 1 pint), your body typically replaces the donated plasma within 24 hours, but it takes about 4 to 6 weeks to replace the blood cells. This restricts the frequency with which donors can contribute their blood. The process by which this replacement occurs is called hemopoiesis, or hematopoiesis (from the Greek root haima- = “blood”; -poiesis = “production”).
Lymphoid and myeloid stem cells do not immediately divide and differentiate into mature formed elements. As you can see in Figure ‘(‘PageIndex{1}’), there are several intermediate stages of precursor cells (literally, forerunner cells), many of which can be recognized by their names, which have the suffix -blast. For instance, megakaryoblasts are the precursors of megakaryocytes, and proerythroblasts become reticulocytes, which eject their nucleus and most other organelles before maturing into erythrocytes.
Sometimes, a healthcare provider will order a bone marrow biopsy, a diagnostic test of a sample of red bone marrow, or a bone marrow transplant, a treatment in which a donor’s healthy bone marrow—and its stem cells—replaces the faulty bone marrow of a patient. These tests and procedures are often used to assist in the diagnosis and treatment of various severe forms of anemia, such as thalassemia major and sickle cell anemia, as well as some types of cancer, specifically leukemia.
The hemangioblast: a historical perspective
An ‘endothelium with hemogenic properties’ was first described as being the precursor to HSCs at the end of the 1800s (reviewed by Adamo and García-Cardeña, 2012). Early observations tied the emergence of these cells to blood flow and vascular development, and, in 1965, Moore and Owen published their observation that all adult hematopoiesis was initiated in extra-embryonic tissues, mainly the yolk sac (Moore and Owen, 1965). Dieterlen-Lievre in 1975 found an intra-embryonic site for hematopoiesis by carrying out experiments in which a quail embryo was transferred into chick blastoderm (yolk sac) (Dieterlen-Lievre, 1975); when HSC formation was traced, there were only HSCs from the quail, indicating that development is intra-embryonic. These experiments led to questions and controversies concerning the origin of HSCs. In 1981, Dieterlen-Lievre and Martin reported that hematopoietic activity in the avian system was only present in the ventrolateral aspect of the aorta (Dieterlen-Lievre and Martin, 1981). In 1993, two groups, Godin and Medvinsky, identified hematopoietic progenitors that appeared in the developing aorta, at the level of the AGM, before appearing in the liver or other hematopoietic organs, demonstrating a link to the endothelium (Godin et al, 1993; Medvinsky et al., 1993). In 1997, Kennedy et al. confirmed these observations in vitro by demonstrating that primitive erythrocytes and other hematopoietic lineages come from a common precursor within the embryoid bodies formed from differentiated embryonic stem cells (ESCs) (Kennedy et al., 1997). These experiments were translated into the human ESC system and confirmed by Zambidis in 2008 (Zambidis et al., 2008). These and other observations led to the theory of the ‘hemangioblast’, which is described as a common precursor for endothelial and hematopoietic cells that retains the ability to give rise to new primitive erythroblasts. Hemangioblasts are different to ‘hemogenic endothelium’, which gives rise to multilineage HSCs/progenitor cells and is therefore responsible for the production of all blood cell types during definitive hematopoiesis. It is important to note, however, that there are now alternative ways to think of the term ‘hemangioblast’. This terminology has been used historically in the literature, but the simple notion of a cell that divides asymmetrically with only two fates is unlikely to be accurate.
Primitive hematopoiesis is largely regulated by two transcription factors, Gata1 and Pu.1 (now known as Sfpi1 in mouse; Spi1b in zebrafish), that exhibit a cross-inhibitory relationship to regulate primitive erythroid and myeloid fates. Gata1 is a master regulator of erythrocyte development (Cantor and Orkin, 2002); Gata1−/− mice die during gestation owing to failed differentiation of pro-erythroblasts into mature erythrocytes. In zebrafish, gata1-expressing cells also express erythrocyte-specific hemoglobin, analyzed by benzidine staining, indicating that genes encoding both alpha and beta embryonic globin (hbbe3, hbbe1.1, hbae3 and hbae1) are expressed in these cells (Detrich et al., 1995). In addition to promoting erythroid-specific gene regulation, Gata1 suppresses myeloid fate; in Gata1 knockdown experiments in zebrafish, blood cells switch to myeloid cells and express myeloid-specific genes, such as pu.1, mpo (myeloperoxidase, now known as mpx; a granulocyte-specific gene) and l-plastin (lcp1). By contrast, Pu.1 is a master regulator of the myeloid cell fate, which includes macrophages and granulocytes (Scott et al., 1994). Similar to the fate switch observed in Gata1 knockdowns, Pu.1 knockdown leads to an increase in gata1 expression in the anterior lateral mesoderm (ALM) and later these cells express hbae1, demonstrating their erythroid switch (Rhodes et al., 2005). As Gata1 and Pu.1 have been shown to interact physically (Cantor et al., 2002), the switch is hypothesized to occur as a result of direct competition between Gata1 and Pu.1 for target genes.
There are many factors and pathways that are important for HSC renewal, but owing to space restrictions, we will focus on two important signaling pathways. There is some controversy, but there is general consensus that these pathways are important for the self-renewal of HSCs.
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