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266 Part IV: Molecular and Cellular Hematology Chapter 18: Hematopoietic Stem Cells, Progenitors, and Cytokines 267

alteration in its conformation. Consistent with the latter notion, certain Collagen Types I, III, V, and VI
epitopes on CD44 have been shown to be inducible, and antibodies to Collagen types I, III, IV, and VI have been identified in LTC or in
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CD44 can alter the adherence of CD34+ cells to marrow stroma. Nev- situ from marrow sections by a number of methods. 35,262 Most of the
ertheless, other data suggests that RHAMM is the primary receptor for marrow-derived collagen types are assembled into long fibrils, which
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hyaluronan. It is also of considerable interest that primitive hemato- form the fine, background reticulin staining seen on marrow biopsies,
poietic cells also express hyaluronan, and that it plays an important role although type IV collagen is assembled into a meshwork seen most
in their lodgment in the marrow and subsequent proliferation. 250 commonly as part of basement membranes. Collagens also interact with
laminins in the marrow. Collagen types I and VI are strong adhesive
Heparan Sulfate substrates for various hematopoietic cell lines and marrow mononu-
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LTCs that support hematopoiesis develop a heparan sulfate proteogly- clear cells, including committed myeloid and erythroid progenitors.
can layer. Immunochemical analysis has shown that marrow stromal Classic collagen receptors on blood cells are of two types, the β integ-
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cell lines synthesize and secrete numerous members of the syndecan rins (α β and α β ) and the nonintegrin glycoprotein VI, present pre-
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family of heparan sulfate, including glypican, betaglycan, and perle- dominantly on platelets.
can. Evidence is accumulating that heparan sulfate-containing prote-
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oglycans may be vital components of the stem cell niche. For example, THE AGING MARROW MICROENVIRONMENT
the structure of the heparan sulfate secreted from stromal cell lines Like the HSC itself (see “Stem Cell Aging” earlier), the HSC niche
that support long-term hematopoiesis are significantly larger and more undergoes several changes with aging. Although the number of
highly sulfated than heparan sulfate from nonsupportive stromal cell osteoblasts decreases, they generate higher levels of ROS, inducing
lines, and when used alone in LTCs, the former can support LTC-IC, p38 MAPK signaling, potentially accounting for the reduction in self-
whereas desulfated heparan sulfate cannot. 251 renewal capacity of HSCs derived from older mammals. The number
of adipocytes increases as a result of the skewed differentiation of aged
Tenascin MSCs; increased adiposity and reduced osteogenesis lead to decreased
Tenascins are large, extracellular matrix (ECM) glycoproteins found in CXCL12 levels in the aged marrow. This finding could be responsible for
several tissues, synthesis of which is upregulated in response to tissue altered HSC mobilization in elderly individuals. In contrast, increased
regeneration. Tenascins are multimeric proteins composed of numerous levels of the CC-chemokine ligand 5 (CCL5; also known as RANTES
modules. For example, tenascin-C is composed of six subunits linked [regulated upon activation, normal T-cell expressed and secreted]), in
like spokes in a wheel by their C-terminal fibrinogen-like domains, each the niche could contribute to the altered myeloid/lymphoid skewing
subunit being composed of multiple epidermal growth factor (EGF)-like seen in HSCs of older individuals. This topic has been reviewed but
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and FN type III modules. Two forms of tenascin of molecular mass (Mr) clearly requires additional study. 138
280 and 220 kDa are also expressed at high levels by marrow stromal
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cells. Marrow cells can adhere to tenascin-C within the fibrinogen- CONTROVERSIES IN HEMATOPOIESIS
like domain and to two sets of the FN type III-like repeats, and when
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so engaged, they undergo a proliferative response. Genetic elimina- LINEAGE FATE DETERMINATION
tion of tenascin leads to modest deficiencies in marrow hematopoietic
progenitor cells, although as the levels of FN in such mice are also One of the most contentious issues in hematopoiesis is the origin of
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reduced, it is unclear if direct tenascin engagement of hematopoietic stem cell commitment to specific blood cell lineages. Two schools of
cells is responsible, or the defect is a result of the secondary reduction of thought exist: extrinsic and intrinsic control. The former, championed
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FN engagement of β integrins. by Metcalf and others, argues that cytokines, ECM, or other stimuli
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instruct the hematopoietic stem or progenitor cell to differentiate into
specific cell types. In contrast, Dexter and others argue that a hierar-
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Laminins chy of transcription factors direct a cell toward a specific lineage, mech-
Laminins are heterotrimeric (αβγ) extracellular proteins that regulate anistically explained by a stochastic rise in one or more of a mutually
cellular function by adhesion to integrin and nonintegrin receptors. antagonistic set of transcription factors, that drive developmental path-
At present, 5 α chains, 3 β chains, and 2 γ chains have been character- ways by enhancing expression of the genes that characterize that path-
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ized, which combine to form at least 12 distinct laminin isoforms. way, and by interfering with the levels or function of the transcription
Laminins containing γ and either β and α chains are expressed in factors that drive the alternate lineage fate choice.
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marrow, but only the latter (laminin-10/11) binds to α β integrin on
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primitive hematopoietic cell lines and to primary human CD34+/ The Case for Transcription Factors
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CD38− stem and progenitor cells. A second, nonintegrin laminin A strong case has been made for intrinsic control of stem cell lineage
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receptor (LR) also binds laminins, as well as other components of the determination. As Enver and colleagues state: “Simply put, the ques-
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ECM, such as FN, collagen, and elastin, and is composed of an acylated tion is this: Is unilineage commitment the result of a cell-autonomous,
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dimer of 32-kDa subunits. Although not an integrin, the LR associ- internally driven program, or rather is it the consequence of a cell
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ates with integrins (e.g., integrin α β ) to modulate laminin binding. responding to an external, environmentally imposed agenda?” These
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Functionally, aminin-10/11 facilitates SDF-1α–stimulated transmigra- and several other investigators argue that the stochastic rise in one or
tion of CD34+ cells, and displays mitogenic activity toward human another lineage determining transcription factor in the multilineage
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hematopoietic progenitor cells. The nonintegrin LR associates with progenitor leads to its ultimate lineage commitment.
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the GM-CSF receptor (GM-CSF-R) to modulate its signaling proper- It is abundantly clear that transcription factors can direct lin-
ties, down-modulating receptor signaling in the absence of laminin, and eage commitment in hematopoietic cells. A partial list of transcrip-
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releasing the inhibition when bound by its ligand. This arrangement tion factors restricted to specific hematopoietic lineages includes
could provide a novel molecular explanation for how laminins affect cell Pax5 (B cells), Ikaros (B/T cells), PU.1 and C/EBPα (myeloid and
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proliferation; whether this physiology extends to other cytokines that B cells), 268,269 GATA1 (erythrocytes and MKs), 132,270 Fli1 (MKs), and
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affect HSCs is under investigation. C/EBPε (granulocytes). A number of loss-of-function studies have
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