Page 98 - Williams Hematology ( PDFDrive )

74 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 75

573
with two other adhesion mediators of HSC homing, CD44 and SCF, are lack all three D cyclins or lack both Cdk4 and Cdk6 kinases have
574
unclear in that antibodies to CD44 or administration of SCF induced specific, lethal hematopoietic failures at the fetal liver stage of definitive
572
HSC mobilization while genetic deficiencies of CD44 or KIT resulted hematopoiesis. In both of these knockout models, the HSC popula-
in decreased G-CSF mobilization. Two chemokine ligands of the tions have little or no loss of numbers, but the multipotent progenitors
480
CXCR2 receptor, IL-8 and GRO-β (KC in mice), induce HSC mobili- are severely reduced, indicating these cell cycle regulators are required
zation within minutes to hours and can synergize with G-CSF, but their for the process that commits the HSC to increased proliferation during
action is more complex in that it is mediated through neutrophils and differentiation. 573,574
their enzymes including MMP-9. 480,563 As they divide, MPPs have progressively restricted lineage poten-
tial, which is regulated by various transcription factors as described
above in the sections on the individual cell types in the marrow. The sin-
CELL PROLIFERATION, APOPTOSIS, gle-lineage progenitors further increase the percentages of their popula-
AND MATURATION tions in active cell cycle so that by the later stages of CFU-E, CFC-G, and
more mature hematopoietic precursor cell development, the majority
575
Irrespective of their location during the postnatal period, HSCs undergo are in the S, G , and M phases. The two potential sources of extracellu-
2
continued self-renewal divisions, but at 3 to 4 weeks of age in mice (cor- lar stimuli that increase hematopoietic cell division are soluble hemato-
responding to 2 to 4 years in humans), they switch to their characteristic poietic cytokines and local interactions of the progenitors with other
cell-cycle quiescence found in adult HSCs. 564,565 This switch appears to be cells and matrix in the marrow. Hematopoietic cytokines include those
an intrinsic event that also decreases the myeloid differentiation poten- produced either in remote organs, such as EPO, or those produced in
564
tial of the HSCs. In the marrow endosteal niche, HSCs have multiple a wide variety of organs, including the marrow, such as TPO, GM-CSF,
576
stimuli that induce cell-cycle quiescence. These stimuli include high and G-CSF. These latter hematopoietic cytokines have multiple effects
concentrations of CXCL12 binding CXCR4 499,503 ; low concentrations of on their target progenitor cells, including the promotion of survival,
CD34, podocalyxin, and endoglycan; TPO binding by MPL 519,520 ; vari- maturation, and migration, that are important for the increased pro-
576
able binding to matrix proteins such as osteopontin, FN, and fibulin, duction and recruitment of the mature cells to sites of inflammation.
that depend upon angiopoetin-1/Tie-2, and SCF/KIT activities. 355,514,516 Among the cytokines, M-CSF is mitogenic, that is, it promotes progres-
Compared to HSCs located outside the endosteal niche, HSCs that are sion from G to S phase, in macrophages and their precursors. The sig-
577
1
closely associated with to the endosteum have greater quiescence, mar- naling from FMS (CSF1R), the M-CSF receptor, which leads to S-phase
row homing, and long-term reconstitution capacity. 566 progression, is mediated by both cyclin D1 and the transcription factor
In murine transplantation studies, cell-cycle status significantly MYC. Among the various cellular interactions of late progenitors and
578
impacts the rate of engraftment and donor hematopoiesis with HSCs in precursors, attachment to central macrophages of EBIs promotes the G
1
378
G phase providing maximal long-term reconstitution, whereas HSCs to S phase transition in erythroid progenitors/precursors. This mito-
0
in G , S, G , or M phases provide minimal engraftment or long-term genic effect of macrophage-erythroid cell interaction is unrelated to the
1
2
reconstitution. 551,564,567 In long-term in vivo labeling with bromodeox- antiapoptotic effect of EPO on the erythroid cells during these stages of
yuridine (BrdU), murine HSC immunophenotypically defined as Lin−, erythroid differentiation. 378
Sca-1+, KIT+, CD150+, CD48−, and CD34− have the greatest recon- Mature hematopoietic cells cease cell division prior to their release
stitution capacity and are located in both endosteal and central areas of from the marrow, but the mechanisms that signal cell cycle arrest in
the marrow. These HSCs are extremely quiescent, dormant, with an hematopoietic cells as they mature are uncertain. Among the poten-
551
estimated division rate of only four or five times over the life of the adult tial mediators of this cell-cycle arrest are Rb and several intracellular
mouse. However, the large majority of them are able to enter cell cycle inhibitors of the cyclin-dependent kinases, specifically the INK4 pro-
and are mobilized within a day or two of stressful stimuli, including teins (p15, p16, p18, p19) that inhibit Cdk4 and Cdk6 and the CIP/KIP
575
551
G-CSF or 5-fluorouracil (5-FU) administration. Dormancy or quies- family of Cdk2 inhibitors (p21, p27, and p57). Rb knockout mice have
cence is resumed upon homing and reestablishing marrow residence, a lethal anemia during fetal liver hematopoiesis that is associated with
indicating that the long-term reconstituting HSCs provide a large persistent progression through cell cycle, but the erythroblast apoptosis
reserve that is able to respond, but only under situations of stress. 551 appears to be related to failure of mitochondrial biogenesis. Under-
570
Dormant or quiescent HSCs are determined to be in G based on standing the activity of p16 INK4a in regulating cell cycle is complicated by
0
lower RNA content and diploid genomic DNA content. 567,568 Entry into its potential role in senescence and apoptosis of HSC. Although p21
579
the cell cycle induces cells into the G phase where a restriction (R) and p27 proteins are proposed as having roles in the TGF-β–induced
1
point is encountered beyond which further progression to S phase and HSC quiescence and in the increased proliferation of later progenitor
580
subsequent transit through G to M phases is irreversible. The sequence stages, Cdk2 knockout mice do not have impaired hematopoiesis,
2
of events and in particular transit through the R point is tightly reg- indicating that other cell-cycle mediators are required for the cessation
ulated by the retinoblastoma tumor-suppressor protein (Rb) and its of proliferation that accompanies terminal differentiation.
paralogs (p107, and p130). 569,570 Rb is regulated by phosphorylation Apoptosis is the major regulator of cellular populations in the
that is catalyzed by cyclin-dependent kinases, Cdk2, Cdk4, and Cdk6. marrow. Because of the exponential expansion of cells in a proliferat-
Cdk4 and Cdk6 are regulated by D-type cyclins (D1, D2, D3), and ing population, cell death has a dramatic effect on the numbers of cells
581
Cdk2 is regulated by E-type cyclins (E1 and E2), at early and late stages, in subsequent generations. Thus, the regulation of hematopoietic
respectively, of the G phase. Hyperphosphorylated Rb releases E2F cell populations by apoptosis provides a mechanism for dramatic and
1
transcription factors that promote entry into S phase by transcription prompt changes in blood cell production. During various stages of dif-
of multiple genes required for replication. 571,572 MPPs, the short-term ferentiation, hematopoietic cells depend upon specific cytokines to pre-
repopulating cells and the colony-forming unit–granulocyte-erythroid- vent apoptosis. 576,581 A wide range of sensitivities to the hematopoietic
monocyte-macrophage (CFU-GEMM), have relatively low rates of cytokines among the dependent cells, as has been demonstrated for ery-
582
proliferation, but they are greatly increased compared to the very infre- throid cells and EPO, results in differential survival that allows for a
quent cell divisions of HSC. The D cyclins and Cdk4 and Cdk6 kinases graded response. Experiments in knockout mice have identified specific
are important in these early progenitor cells because knockout mice that proteins in the Bcl-2 family as principal regulators of the intrinsic or
Kaushansky_chapter 05_p0051-0084.indd 74 9/19/15 12:11 AM