Fig. 2.10. A, Simplified schematic showing the cell fate choices open to a hematopoietic stem progenitor cell (HSPC). Cells can either be quiescent, or undergo apoptosis or divide. Cell division can either be symmetrical self-renewing cell division (the two daughter cells have the same potential as the parental cell), asymmetrical (daughter cells produce one cell with the same potential as the parental cell and one cell that is more differentiated), or symmetrical differentiation cell division (the two daughter cells are more differentiated than the parental cell). B, The cell fate choices taken by an HSPC at different stages of hematopoietic differentiation. Hematopoietic stem cells (HSCs) are mainly quiescent and self renew (either through symmetrical self-renewal or asymmetric division), progenitors are highly proliferative, have less selfrenewal, and are more likely to differentiate (i.e. more likely to have symmetrical differentiation divisions or asymmetrical divisions). As cells terminally mature the focus is on divisions that lead to terminal differentiation (symmetrical differentiation divisions) and exit from the cell cycle, finally leading to apoptosis. LT-HSC, long-term hematopoietic stem cell; ST-HSC, short-term hematopoietic stem cell; LMPP, lymphoidprimed multipotential progenitors; MEP, megakaryocyte-erythroid progenitor; GMP, granulocyte-macrophage progenitors; MLP, multipotential lymphoid progenitors; MEP, megakaryocyte-erythroid progenitor; MkP, megakaryocyte progenitor. 图 2.10.A, 显示造血干祖细胞（HSPC）细胞命运选择的简化示意图。细胞既可静止，也可凋亡或分裂。细胞分裂既可以是对称的自我更新细胞分裂（两个子细胞与亲代细胞具有相同的潜能），也可以是不对称的细胞分裂（子细胞产生一个与亲代细胞具有相同潜能的细胞和一个分化程度较高的细胞），还可以是对称的分化细胞分裂（两个子细胞的分化程度高于亲代细胞）。B，造血干细胞在造血分化不同阶段的细胞命运选择。造血干细胞（HSCs）主要处于静止状态，可自我更新（通过对称自我更新或不对称分裂）；祖细胞增殖能力强，自我更新能力较弱，更有可能分化（即更有可能进行对称分化分裂或不对称分裂）。当细胞终末成熟时，重点是导致终末分化（对称分化分裂）和退出细胞周期的分裂，最终导致细胞凋亡。LT-HSC，长期造血干细胞；ST-HSC，短期造血干细胞；LMPP，淋巴母细胞多潜能祖细胞；MEP，巨核细胞-红细胞祖细胞；GMP，粒细胞-巨噬细胞祖细胞；MLP，淋巴母细胞多潜能祖细胞；MEP，巨核细胞-红细胞祖细胞；MkP，巨核细胞祖细胞。
TFs is shown in Fig. 2.11. Although a complete description of the function of these proteins is not possible here, some of the key points that arise from these studies are as follows: 图 2.11 显示了 TF 蛋白的功能。虽然在此不可能对这些蛋白质的功能进行完整的描述，但这些研究得出的一些要点如下：
TFs are divided into families that have similar proteins domains. TFs 被划分为具有相似蛋白质结构域的家族。
They often bind DNA and interact with other proteins (other TFs and proteins that control transcription) via specific domains. 它们通常与 DNA 结合，并通过特定结构域与其他蛋白质（其他 TF 和控制转录的蛋白质）相互作用。
TFs work in combinations to both activate and repress the expression of a large number of genes. TFs 以组合方式发挥作用，激活和抑制大量基因的表达。
TFs are required at discrete stages of hematopoiesis and any one TF often functions at multiple stages within one lineage and can function in more than one lineage. 造血过程的各个阶段都需要 TF，任何一种 TF 通常在一个血系的多个阶段发挥作用，而且可以在多个血系中发挥作用。
Ultimately, TFs work in complicated networks that can be modeled much like semiconductor/computing networks. TFs work in negative feedback loops, feedforward loops, and cross-antagonistic loops to mention just three such types of interaction. 归根结底，TFs 是在复杂的网络中工作的，其模型与半导体/计算机网络非常相似。TF 在负反馈环路、前馈环路和交叉拮抗环路中工作，这只是其中三种类型的相互作用。
The function of TFs helps regulate the cell’s potential to make blood cells of different lineages, proliferate, undergo apoptosis, and self renew. TFs 的功能有助于调节细胞制造不同血系的血细胞、增殖、凋亡和自我更新的潜力。
More specifically, the TFs SCL/TAL1 and LMO2 are required to specify HSCs from mesoderm; RUNX1 (AML1) specifies HSCs from hemogenic endothelium; and RUNX1, TAL1, TEL1, MLL, and GATA2 are required to maintain stem cells once they have been specified. In myelopoiesis, the TFs PU.1, the C/EBP family (C/EBPo and C/EBPe), GFI-1, EGR-1, and NAB2 all promote the granulocyte-macrophage lineage programs. GATA2 is required in stem/early progenitor cells but is also required for mast cells and in the early phases of megakaryocyte-erythroid lineage maturation and late stages of megakaryocyte differentiation. Working with GATA2 to promote erythropoiesis and megakaryopoiesis are GATA1, FOG1, SCL, KLF4, p45NF-E2, and FlI-1. In early lymphoiesis, the TF Ikaros is required. In B lymphopoiesis, the TFs E2A (and its family members), EBF, and PAX5 are required, and finally, the TF BLIMP1 is necessary for plasma cell formation. In T-cell maturation, Notch signaling activates the TF CSL, which works with the TFs RUNX1, GATA3, T-BET, NFATc, and FOXP3. 更具体地说，TFs SCL/TAL1和LMO2需要从中胚层指定造血干细胞；RUNX1（AML1）需要从造血内皮指定造血干细胞；RUNX1、TAL1、TEL1、MLL和GATA2需要在干细胞被指定后维持干细胞。在骨髓造血过程中，TFs PU.1、C/EBP 家族（C/EBPo 和 C/EBPe）、GFI-1、EGR-1 和 NAB2 都能促进粒细胞-巨噬细胞系的形成。干细胞/早期祖细胞需要 GATA2，肥大细胞、巨核细胞-红细胞系成熟的早期阶段和巨核细胞分化的晚期阶段也需要 GATA2。与 GATA2 共同促进红细胞生成和巨核细胞生成的还有 GATA1、FOG1、SCL、KLF4、p45NF-E2 和 FlI-1。在早期淋巴形成过程中，需要 TF Ikaros。在 B 淋巴细胞形成过程中，需要 TF E2A（及其家族成员）、EBF 和 PAX5，最后，TF BLIMP1 是浆细胞形成的必要条件。在 T 细胞成熟过程中，Notch 信号激活 TF CSL，CSL 与 TF RUNX1、GATA3、T-BET、NFATc 和 FOXP3 共同发挥作用。
Of note, the TF SCL/TAL1, MLL, RUNX1, LMO2, PU.1, C/EBPo alpha\alpha, PAX5, E2A, GATA2, and GATA1 are all implicated in the pathogenesis of human leukemia. 值得注意的是，TF SCL/TAL1、MLL、RUNX1、LMO2、PU.1、C/EBPo alpha\alpha 、PAX5、E2A、GATA2 和 GATA1 都与人类白血病的发病机制有关。
THE HEMATOPOIETIC NICHE 造血龛
It has been long appreciated that HSPCs require specialized anatomical locations called niches to survive and exercise their cell fate options. Niches are likely to exist in all hematopoietic organs. Most of the work has concentrated on the bone marrow niche and lessons have been learnt from a number of organisms, especially mice. In the niche a number of extrinsic inputs influence hematopoietic cells (Fig. 2.12). The niche consists of a physical architecture: the cells surrounding hematopoietic cells (such as stromal cells, adiopocytes, endothelial and perivascular cells of the vasculature and osteoblasts) and the extracellular matrix (Table 2.1 and Fig. 2.13). Humoral inputs include cytokines. Paracrine signaling inputs (molecules that act over a short range) include chemokines, such as CXCL12 that interacts with the receptor CXCR4 on hematopoietic cells, soluble WNT (Wingless-related) proteins, NOTCH modulators, fibroblast 长期以来，人们一直认为 HSPCs 需要专门的解剖位置（称为龛位）才能存活并行使其细胞命运选择权。所有造血器官都可能存在龛位。大部分研究工作都集中在骨髓壁龛上，并从许多生物，尤其是小鼠身上吸取了经验教训。在骨髓龛中，一些外来输入对造血细胞产生影响（图 2.12）。骨髓龛由物理结构组成：造血细胞周围的细胞（如基质细胞、血管内皮细胞、血管周围细胞和成骨细胞）以及细胞外基质（表 2.1 和图 2.13）。体液输入包括细胞因子。旁分泌信号输入（短距离作用的分子）包括趋化因子（如与造血细胞上的受体 CXCR4 相互作用的 CXCL12）、可溶性 WNT（与无翼鸟有关的）蛋白、NOTCH 调节剂、成纤维细胞、细胞因子和细胞膜（表 2.1 和图 2.13）。
Fig. 2.I I. Schematic representation of hematopoiesis and where key hemat-opoietic-specific transcription factors (TFs) have nonredundant functions as revealed by gene deletion studies in mice. Thus, for example, the TFs GATA2, RUNXI,SCL/TALI, LMO2, and ETV6 are all critically required in hematopoietic stem cells (HSCs), and loss of function of these genes causes a block hematopoietic differentiation at the HSC level, showing they are required for HSC function. Similarly, the other TFs shown downstream of HSC are required 图 2.I I.造血示意图，以及小鼠基因缺失研究显示的关键造血特异性转录因子（TFs）的非冗余功能。例如，GATA2、RUNXI、SCL/TALI、LMO2 和 ETV6 都是造血干细胞（HSCs）所必需的转录因子，这些基因的功能缺失会导致造血干细胞水平的造血分化受阻，表明它们是造血干细胞功能所必需的。同样，造血干细胞下游的其他 TFs 也是造血干细胞功能所必需的。
Fig. 2.12. Stem cells are thought to reside in specialized regions of the bone marrow, or “niches.” The factors that regulate stem cell biology include the architectural space, physical engagement of the cell membrane with tethering molecules on neighboring cells or surfaces, signaling interactions at the interface of the stem cell and its niche, paracrine and endocrine signals from local or distant sources, neural inputs, and metabolic products of tissue activity. Source: Scadden DT. Nature 2006;441:I075-I079. Reproduced with permission from Springer Nature. 图 2.12.干细胞被认为居住在骨髓的专门区域或 "龛 "中。调节干细胞生物学的因素包括建筑空间、细胞膜与邻近细胞或表面系链分子的物理接触、干细胞与其龛位界面的信号相互作用、来自本地或远方的旁分泌和内分泌信号、神经输入以及组织活动的代谢产物。来源：Scadden DT：斯卡登 DT.自然》2006；441：I075-I079。经 Springer Nature 授权转载。
later in hematopoiesis at the stages where the TFs are shown. LT-HSC, longterm hematopoietic stem cell; ST-HSC, short-term hematopoietic stem cell; MPP, multipotential progenitors; LMPP, lymphoid-primed multipotential progenitor; MLP, multipotential lymphoid progenitor; GMP, granulocytemacrophage progenitor; MEP, megakaryocyte-erythroid progenitor; Ery ^("P, "){ }^{\text {P, }} erythroid progenitor; MkP, megakaryocyte progenitor. 在造血过程的后期，TFs 的位置会显示出来。LT-HSC，长期造血干细胞；ST-HSC，短期造血干细胞；MPP，多潜能祖细胞；LMPP，淋巴引诱多潜能祖细胞；MLP，多潜能淋巴祖细胞；GMP，粒细胞-巨噬细胞祖细胞；MEP，巨核细胞-红细胞祖细胞；Ery ^("P, "){ }^{\text {P, }} 红细胞祖细胞；MkP，巨核细胞祖细胞。
TABLE 2.I. HEMATOPOIESIS DEPENDS ON THESE STROMAL CELLS AND EXTRACELLULAR MATRIX 表 2.I. 造血依赖于这些基质细胞和细胞外基质
growth factors (FGFs), and members of the Hedgehog family (Fig. 2.14). The roles of cytokines, paracrine factors and the downstream signaling pathways in hematopoiesis are discussed in Chapters 1 and 3. 生长因子（FGFs）和刺猬家族成员（图 2.14）。细胞因子、旁分泌因子和下游信号通路在造血中的作用将在第 1 章和第 3 章中讨论。
Fig. 2.13. Mobilization, homing, and lodging. Schematic diagram showing some of the factors involved in these processes. Hematopoietic stem cells (HSCs) bound to the niche are mobilized into peripheral blood by growth factor therapy (G-CSF) or chemotherapy (cyclophosphamide or other regimens). Once in the bloodstream they migrate to all hematopoietic organs, including the spleen (as shown). They home to the bone marrow and bind to a number of cell surface molecules, including endothelial- (E-) and platelet- (P-)selectin, P-selectin 图 2.13.调动、归巢和栖息。示意图显示了这些过程中涉及的一些因素。通过生长因子疗法（G-CSF）或化疗（环磷酰胺或其他疗法），结合在龛位的造血干细胞（HSCs）被动员到外周血中。一旦进入血液，它们就会迁移到所有造血器官，包括脾脏（如图所示）。它们以骨髓为家，并与许多细胞表面分子结合，包括内皮（E-）和血小板（P-）选择素、P-选择素、E-选择素和P-选择素。
glycoprotein ligand I (PSGLI), very late antigen 4 (VLA4) and VLA5, and lymphocyte function-associated antigen I (LFAI).After entering the marrow they lodge in the niche, a process that is regulated by membrane-bound stem cell factor (SCF), CXC-chemokine ligand 12 (CXCLI2) and its receptor CXCchemokine receptor 4 (CXCR4), osteopontin (OPN), hyaluronic acids, and their corresponding receptors. Source:Wilson A, Trumpp A. Nat Rev Immunol 2006;6:93-106. Reproduced with permission from Springer Nature. 这些抗原包括糖蛋白配体 I（PSGLI）、晚期抗原 4（VLA4）和 VLA5 以及淋巴细胞功能相关抗原 I（LFAI）。进入骨髓后，它们会栖息在龛位中，这一过程受膜结合的干细胞因子（SCF）、CXC-凝血因子配体12（CXCLI2）及其受体CXC-凝血因子受体4（CXCR4）、骨生成素（OPN）、透明质酸及其相应受体的调节。资料来源：Wilson A, Trumpp A. Nat Rev Immunol 2006;6:93-106。经 Springer Nature 授权转载。
Fig. 2.14. A, The bone marrow niche, which, in part, consists of sinusoidal endothelial cells, helps control hematopoietic stem cell (HSC) fate. HSCs can be in G_(0)\mathrm{G}_{0} or can enter the cell cycle to divide symmetrically or asymmetrically (divisional asymmetry) to self renew and/or to produce more differentiated cells such as multipotential progenitors (MPPs). HSCs can also migrate into and out of the niche (environmental asymmetry). The components of the niche (niche players) are listed below. B, An HSC anchored into the niche via TIE2/TEK binding to its ligand angiopoietin-I (ANG-I) on sinusoidal endothelial cells (SNO cells) and CXC-chemokine ligand I2 (CXCLI2) on SNO cells binding to its receptor CXCR4. 图 2.14A、骨髓龛（部分由静脉窦内皮细胞组成）有助于控制造血干细胞（HSC）的命运。造血干细胞可以处于 G_(0)\mathrm{G}_{0} 状态，也可以进入细胞周期进行对称或不对称分裂（分裂不对称），以自我更新和/或产生更多分化细胞，如多潜能祖细胞（MPPs）。造血干细胞还可以迁入或迁出生态位（环境不对称性）。下面列出了生态位的组成成分（生态位参与者）。B，造血干细胞通过 TIE2/TEK 与窦状内皮细胞（SNO 细胞）上的配体血管生成素-I（ANG-I）结合，以及 SNO 细胞上的 CXC-凝血因子配体 I2（CXCLI2）与其受体 CXCR4 结合，锚定到龛位中。
More recently it has begun to be appreciated that metabolic inputs (such as ionic calcium levels regulated in part by surrounding osteoblasts) and neural inputs (signaling from the autonomic nervous system) may also regulate hematopoietic stem/early progenitor behavior. The regulation of stem/ progenitor cells is in part controlled by cell-cell contacts that are mediated by cell surface adhesion molecules that regulate the interaction of hematopoietic cells with surrounding niche cells and are important in the retention and release of HSPCs. This is important in controlling the trafficking of HSPCs both 最近，人们开始认识到，新陈代谢输入（如离子钙水平，部分由周围成骨细胞调节）和神经输入（来自自主神经系统的信号）也可能调节造血干细胞/早祖细胞的行为。干细胞/祖细胞的调控部分受细胞-细胞接触的控制，这种接触由细胞表面粘附分子介导，可调控造血细胞与周围龛位细胞的相互作用，并对 HSPC 的保持和释放非常重要。这对控制 HSPCs 的贩运非常重要，包括
normally and in situations such as therapeutic stem/progenitor cell mobilization (Fig. 2.14). 正常情况下，以及在治疗性干细胞/祖细胞动员等情况下（图 2.14）。
In addition to the marrow niche there are likely to be other niches that we know even less about. For example, in development the fetal liver is a critical site of hematopoiesis and it is likely the niche here will be different from that in the bone marrow. In addition, there is increasing work studying how modifying the niche may modify the nature of the cell divisions (symmetrical-versus-asymmetric, Fig. 2.9) that HSCs undergo (Fig. 2.11A). 除了骨髓生态位，我们对其他生态位的了解可能更少。例如，在发育过程中，胎儿肝脏是造血的关键场所，这里的生态位很可能不同于骨髓中的生态位。此外，越来越多的研究工作正在探讨改变生态位如何改变造血干细胞所经历的细胞分裂的性质（对称-非对称，图 2.9）（图 2.11A）。
