Mammalian hematopoiesis occurs in several waves, which are separated temporally and spatially and produce different cell types: a transient first “primitive” is followed by a “prodefinitive” and then a “definitive” wave, which persists through life.[1-3]While most of the evidence is derived from the mouse, data from humans, albeit limited, point to a very comparable hematopoietic program.[4,5]

During embryogenesis, the hematopoietic cells of the first, primitive wave are formed when cells from the epiblast that constitute the prospective mesoderm ingress and migrate through the primitive streak between the endoderm and ectoderm, both in the embryo proper and in the extraembryonic yolk sac (YS). In the latter, mesodermal cells aggregate to form blood islands surrounded by visceral endodermal cells on mouse embryonic day (E) 7 to 7.5. The close proximity of erythroid cells and vascular endothelium in YS blood islands, their origin from mesoderm, and their simultaneous differentiation led to the proposal of a common precursor, the hemangioblast, over a century ago.[6,7] In support of this hypothesis, a spontaneous zebrafish mutant, cloche (named for its bell-shaped heart because of the loss of endothelium), lacks both vasculature and hematopoietic cells but no other mesodermal lineages such as cardiac progenitors.[8,9] The gene mutated in cloche was recently cloned and encodes a PAS (PER-ARNT-SIM) domain–containing basic helix-loop-helix (bHLH) transcription factor (npas4l), which belongs to the same class that also includes the aryl hydrocarbon receptor and hypoxia-induced factor (HIF)-1α.[9a] Also, mice lacking FLK1 (VEGFR2, a receptor for vascular endothelial growth factor), expressed on endothelial (progenitor) cells, fail to develop both vascular endothelium and blood islands during embryogenesis.[10,11] Indeed, gene tracing studies in mouse and human embryonic stem cell cultures have identified a progenitor with both hematopoietic and endothelial potential.[12-14]

Primitive hematopoiesis encompasses the generation of primarily large erythroid cells and primitive macrophages.[15-17] Following this initial wave, beginning at mouse E8.25, erythromyeloid progenitors (EMPs) are generated as prodefinitive progenitors.[18,19] Both waves arise transiently in the YS during a time comparable to the first trimester in humans,[20] but the cells lack the capacity for self-renewal and multilineage differentiation present in definitive HSCs. The emergence of EMPs during development is presaged by ckit+ EMP precursors that are characterized by the expression of toll-like receptor 2 (TLR2) at E7.5.[21] Three lineage-tracing studies recently demonstrated that embryonic erythropoiesis is sustained completely by YS EMPs, rather than HSC-derived progenitors.[22] Remarkably, Hoxa neg/low Kit+CD41+CD16/32+ HSC-independent EMPs from the YS have also been shown to give rise to NK cells with cytotoxic capability,[23] and YS EMPs produce osteoclast precursor cells that create space for post-natal BM hematopoiesis.[24,25] Interestingly, epidermal γδ T cells, also known as dendritic epidermal T cells, function in the adult epidermis, and are also derived from YS progenitors.[26] Utilizing single cell transcriptomic analysis and single cell cultures of YS-derived myeloid progenitors, Bian et al. recently provided a comprehensive characterization of the spatiotemporal dynamics of early macrophage development from YS progenitors during embryo genesis.[27] This study provides unprecedented insight into the distinct biology of tissue resident macrophages that are derived from YS progenitors. Importantly, Stremmel et al.[28] day 8.5 through day 12.5 via the bloodstream into embryonic tissues where they take up long-term residence.

Definitive HSCs capable of long-term (LT), multilineage reconstitution of irradiated adult recipient mice appear at E10.5 in the intraembryonic region encompassing the aorta, gonads, and mesonephros (AGM), in particular in hematopoietic intra-aortic clusters in the ventral wall of the dorsal aorta.[3,29-31] Then, within a remark ably short period of 1.5 days during embryonic development, virtually all HSCs are generated that will replenish the hematopoietic system throughout fetal and adult life.[32-33] Studies by Ganuza et al.[34] utilizing cultured 2 to 7 somite pairs (sp) murine embryonic explants and 2 to 7 sp YS explants confirmed that the embryo, not the YS, is the source of definitive HSCs. Several complementary studies using lineage tracing experiments in both mice and zebrafish have demonstrated that within the dorsal aorta, hemogenic endothelial cells (ECs) are the direct precursors of definitive HSCs.[33,35-39] In a process known as endothelial-to-hematopoietic transition (EHT), HSCs bud off the hemogenic endothelium to form intra-aortic hematopoietic clusters from which they are released into circulation. Interestingly, while the AGM gives rise to HSCs, it is not the site of hematopoietic differentiation.[40] Rather, HSCs colonize the fetal liver where they expand and then differentiate (Ref. [41] and references therein).

Recent advances in single cell labeling and single cell transcriptomic analysis has allowed the isolation and characterization of a population of “pre-HSCs” during murine development.[42] CD45+ pre-HSCs in the AGM were shown to have a unique molecular signature and activation of mechanistic target of rapamycin (mTOR) was reported to be indispensable for the emergence of HSCs.[41] Separate studies which evaluated ex vivo maturation of HSCs from pre-HSCs showed that ex vivo matured HSCs and fetal liver HSCs express programmed death ligand 1 (PDL1), among other immune response genes, although PDL1 expression was not required for engraftment of embryonic HSCs.[43]

Evidence from studies in mice suggests that some definitive hematopoiesis also occurs at sites other than the AGM. By E12 the fetal liver contains more HSCs than can be accounted for by HSCs generated in the AGM alone.[44] Quantitative analysis of HSC distribution showed that both YS[44] and placenta [45,46]generate definitive HSCs that migrate to the liver and other hematopoietic sites.[47] Lastly, a c-Myb- and thus HSC-independent cell lineage that emerges between E8.5 and E9.5 in the YS has recently been shown to give rise to YS macrophages and later on to tissue macrophages in brain (microglia), liver (Kupffer cells), and skin (Langerhans cells).[48]

Human induced pluripotent stem cell models and studies of zebrafish have suggested that a population of immune precursors may originate directly from hemogenic endothelium rather than HSCs.[49,50] Utilizing a RAG1:GFP human reporter system, Motazedian et al.[50] showed that early RAG1+ cells could differentiate into CD4+CD8+ T cells, also possessed B-cell, myeloid, and erythroid potential, while also expressing endothelial markers, and resided within CD31+ endothelial structures. The authors concluded that a wave of T-cell development might originate directly from hemogenic endothelium via a RAG1+ intermediate population.[50] Utilizing a novel technique called “ScarTrace,” a single cell sequencing strategy to quantify the clonal history and cell type of thousands of cells in different organs of the developing zebrafish, Alemany et al.[51] identified a novel population of immune cells in the zebrafish fin that had a distinct clonal origin from other hematopoietic cells. In keeping with these studies, Tian et al.[49] utilized temporal-spatial fate mapping analysis and time-lapse imaging to show that a wave of T lymphopoiesis could be detected in the developing zebrafish, arising from ventral endothelium in the AGM and posterior blood islands. This generation of CD4+ T cells is transient and occurs only in the early larval stage, and is later replaced by HSC-dependent T cells of all subtypes.[49] Taken together, these studies provide the impetus for further exploration of evidence for HSC-independent immune cell generation during mammalian development.[52]

References

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اخر الاخبار

اخبار العتبة العباسية المقدسة

العتبة العباسية المقدسة تواصل إقامة مجلسها العزائي بذكرى أربعين الإمام الحسين (عليه السلام)

مشروع التبليغ الحوزوي يستضيف وفدًا أكاديميًّا من جامعة واسط

مع بلوغ زيارة الأربعين ذروتها.. قسم رعاية الصحن يستنفر ملاكاته لتقديم الخدمات للزائرين

المجمع العلمي: 14 محطة قرآنية يشرف عليها 247 معلماً قدمت خدماتها لزائري الأربعين في بابل

المزيد

الآخبار الصحية

حجم جزء محدد من الجسم يعكس الصحة العامة ومخاطر الأمراض

تفشي عدوى بكتيرية بفرنسا يحتمل ارتباطها بنوع من الجبن الطري

دراسة حديثة تكشف ما تفعله الشاشات بـ"قلوب الأطفال" !

متلازمة المبنى المريض.. هكذا يتحول تكييف الهواء إلى خطر صحي ؟؟

المزيد

الآخبار التكنلوجية

كيف تتعامل مع حرارة الطقس أثناء القيادة؟

لماذا يجب عليك إيقاف تكييف السيارة قبل إطفاء المحرك؟

دراسة تكشف سببا محتملا وراء زيادة خطر إصابة الأطفال بالتوحد

تشيلي.. العثور على متحجرة حيوان ثديي صغير من زمن الديناصورات

المزيد

مواضيع ذات صلة

Human Hematopoietic Stem Cells

نقي العظم (النخاع العظمي) Bone marrow

تكوين الدم Haematopoiesis

Gastrointestinal decontamination

تطبيقات البرايون ودوره المثير في مفهوم العقيدة المركزية

تصوير الأوعية التاجية

أدواء البريونات

Stages of Neutrophil Differentiation

Types of Bone

Elements Comprising Bone Tissue

تخفيض مستوى الكولسترول يخفض الأزمات القلبية

تخطيط القلب الكهربائي أثناء الإجهاد