1. Introduction
Adult hematopoietic stem cells (HSCs) ensure the maintenance of the HSC pool via their self-renewal capacity, and replenish mature cells throughout life via their proliferation and differentiation into lineage-restricted cells [1, 2]. HSCs are the only stem cells that have been used in the clinic to treat diseases, such as leukemia, germ cell tumors, and congenital immunodeficiencies. Since HSCs were first proposed [3], advances in multicolor flow cytometry have allowed the purification of mouse HSCs close to homogeneity. Several groups have succeeded in long-term hematopoietic reconstitution by transplanting a single lineage of HSCs (e.g., CD34low/- Kit+ Sca-1+ lineage marker-negative cells and CD150+ CD48- Kit+ Sca-1+ lineage marker-negative cells), providing direct proof of the existence of HSCs [4-7]. More recently, two groups analyzed the cycling status of HSCs by monitoring their proliferation rate over several months in vivo. The results of these studies suggested the presence of dormant HSCs that divide only about five times throughout the mouse life span [8, 9].
In the bone marrow (BM), HSCs are located in a specialized microenvironment, called the niche. Under steady-state conditions, signals from niches maintain some HSCs in a dormant state. Acquisition of dormancy is critical for the preservation of the self-renewal ability of HSCs and for the prevention of premature stem cell exhaustion [10-12]. However, in response to external stresses, such as bleeding, myeloablative chemotherapy and total body irradiation, HSCs proliferate extensively to produce very large numbers of primitive progenitor cells, thereby enabling rapid hematological regeneration [13]. Once recovery from myelosuppression or other stresses has been achieved, the activated HSCs return to a quiescent state via a number of negative feedback mechanisms [14]. This ability is a hallmark of HSCs and is fundamental for the maintenance of hematopoietic function throughout the life of the organism. Although this property has long been recognized and is very important for organism survival, the molecular basis underlying how HSCs react to a hematologic emergency remains enigmatic. However, some key players have been identified. In this chapter, we briefly review the recent advances in our knowledge of HSC cell-intrinsic and cell-extrinsic regulators that are critical for hematopoietic regeneration under stress hematopoiesis.
2. Cell-intrinsic factors
2.1. Hemeoxygenase-1
Heme plays many important roles, such as in the promotion of proliferation and differentiation of hematopoietic progenitor cells (HPCs) [15], and in the stimulation of hematopoiesis [16, 17]. Heme oxygenase (HO) catalyzes the degradation of heme. HO-1, encoded by the
2.2. PSF-1
PSF-1, a partner of sld five-1, forms a multiprotein complex, termed GINS. The GINS complex contains Psf2, Psf3, and Sld5 in addition to Psf-1 [19-21]. All genes encoding this complex are evolutionally conserved and are essential for cell growth [22]. Ueno et al isolated the mouse orthlog of
2.3. Necdin
Necdin belongs to the melanoma antigen family of molecules, whose physiological roles have not been well characterized [25]. Necdin was originally identified as a gene product induced in neurally differentiated embryonal carcinoma cells [26]. Interestingly, recent genetic analyses demonstrate that aberrant genomic imprinting of
2.4. Slug
Slug is a member of the highly conserved Slug/Snail family of zinc-finger transcriptional repressors found in diverse species ranging from C. elegans to humans. SLUG is a target gene for the E2A-HLF chimeric oncoprotein in pro-B cell acute leukemia [39]. Slug is highly expressed in immature hematopoietic cells, and a study using
2.5. Erg
The E-twenty-six (ETS)-related gene (ERG) belongs to the ETS family of transcription factors [44]. ERG rearrangement has been reported in acute myeloid leukemia (AML) [45] and Ewing sarcoma [46]. ERG overexpression has also been observed in prostate cancer [47]. A recent study revealed that overexpression of ERG is an adverse prognostic factor in AML with a normal karyotype [48]. More recently, the role of Erg in hematopoietic development and normal hematopoiesis was investigated.
3. Cell-extrinsic factors
The interaction between HSCs and their microenvironment (niche) is essential for HSC maintenance, self-renewal, and survival. However, recent studies have revealed that the cell-extrinsic factors provided by the BM niche are also important for HSC responses during hematopoietic regeneration. Some key players have been identified.
3.1. Connexin-43
The exchange of ions, metabolites, and other small molecules (up to ~1,200 Da) occurs via gap junctions. Gap junctions are configured by a large family of proteins known as connexins (Cxs). In the connexin family, connexin-43 (Cx43) is highly expressed in BM stromal cells [59], endothelial cells [7], osteoblasts [60], and mesenchymal stem cells [61]. HSCs also express Cx43 [36]. Cx43-deficiency in the BM (
The same group also investigated the role of Cx43 in the BM osteoblastic niche. For this, Gonzalez-Nieto et al used conditionally osteoblast lineage-specific Cx43-deficient mice:
3.2. TIMP-3
Metalloproteinases (MMPs) modulate the extracellular matrix (ECM) environment [69-71]. Several studies have indicated that MMP-9 and MT1-MMP are important for the cleavage and inactivation of the KIT ligand (Stem cell factor: SCF) and CXCL12 during G-CSF-induced mobilization and hematopoietic recovery after cytotoxic stress in the BM [72-75]. Tissue inhibitors of the metalloproteinase (TIMP) family consist of four members (TIMP-1 to -4), all of which are endogenous regulators of metalloproteinases (MMPs) [76, 77]. Although TIMPs were initially identified as inhibitors of MMPs, recent findings suggest that they might have more diverse functions [78, 79]. Previous work suggested that TIMP-1 deficiency or enforced expression of TIMP-1 or TIMP-2 does not alter steady-state hematopoiesis and stress hematopoiesis, such as those induced by G-CSF stimulation and myelotoxic insult, respectively [80]. However, Rossi et al recently found that increased expression of p53 in
Among TIMP family members, TIMP-3 has unique properties. TIMP-3 binds firmly to ECM, a disintegrin [82-84], and inhibits metalloproteinase domain-containing proteins, such as ADAMs and ADAMTSs (ADAM proteins with Thrombospondin Motifs) [85]. Nakajima et al found decreased expression of TIMP-3 in immune suppressor factor (ISF)/short form of ISF (ShIF)-transfected cell lines, and partial reduction of HSC-supporting activity following the restoration of TIMP-3 expression in stromal cells expressing ISF [86]. These authors also investigated the role of TIMP-3 in HSC regulation. TIMP-3 expression in BM was increased after 5-FU injection, and addition or overexpression of TIMP-3 resulted in enhanced proliferation of HSCs in vitro. BM regeneration after myelotoxic stress was impaired in TIMP-3-deficient mice, but was accelerated by enforced expression of TIMP-3 in vivo [87]. Another group also studied the role of TIMP-3 in hematopoiesis. They found that TIMP-3 was highly expressed in the endosteal region of the BM, the HSC niche, whereas its expression was low in HSCs and progenitor cells. They also examined the effect of human TIMP-3 (huTIMP-3) overexpression in HSCs in vivo. TIMP-3 overexpression resulted in increased myelopoiesis and decreased lymphopoiesis. Consistent with the study of Nakajima et al [87], HSC proliferation was increased by huTIMP-3 overexpression in vitro and in vivo [88]. These results suggest that TIMP-3 is important for the cellular response to myelosuppression.
3.3. Tenascin-C
Tenascin-C (TN-C) is a large extracellular matrix (ECM) glycoprotein that is expressed mainly in the developing embryo [89]. In the adult BM, expression of TN-C is restricted to the endosteal region [90, 91]. Although TN-C-deficient mice exhibit grossly normal development, the colony-forming capacity of
4. Conclusions
In this chapter, we have briefly summarized regulators that have recently been shown to be involved in the control of HSCs and progenitors during the hematopoietic regeneration phase. Recent studies have revealed that, when myelopoiesis is compromised following infection, HSC proliferation involves not only the factors described in this review, but also inflammatory signaling molecules such as interferons [94-96], tumor necrosis factor-α [97, 98], and Toll-like receptors [99-101]. Because HSC proliferation potential is critical for organism survival during stress conditions, further understanding of the mechanism of stem cell activation will be needed before stem cells can be used in regenerative medicine.
Acknowledgments
This work was supported by a Grant-in-Aid for Young Scientists to Y.K. (no. 23791083) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.
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