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Keywords:

  • Stemness;
  • Hematopoietic stem cell;
  • Microenvironment;
  • Epigenetic;
  • Intrinsic regulators

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

Hematopoietic stem cells (HSCs) are characterized by their unique function to produce all lineages of blood cells throughout life. Such tissue-specific function of HSC is attributed to their ability to execute self-renewal and multilineage differentiation. Accumulating evidence indicates that the undifferentiated state of HSC is characterized by dynamic maintenance of chromatin structures and epigenetic plasticity. Conversely, quiescence, self-renewal, and differentiation of HSCs are dictated by complex regulatory mechanisms involving specific transcription factors and microenvironmental crosstalk between stem cells and multiple compartments of niches in bone marrows. Thus, multidimensional regulatory inputs are integrated into two opposing characters of HSCs—maintenance of undifferentiated state analogous to pluripotent stem cells but execution of tissue-specific hematopoietic functions. Further studies on the interplay of such regulatory forces as “cell fate determinant” will likely shed the light on diverse spectrums of tissue-specific stem cells. STEM CELLS2012;30:82–88


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

The Concept of Stem Cell “State” As Applied to Hematopoietic Stem Cells

The adult body is now known to retain multiple types of stem cells that are dedicated to the life-long maintenance and potential regeneration of a wide range of specific tissues. These cells not only have tissue-specific features such as location, growth factor responsiveness, cell surface characteristics, and differentiation potential but also share key functional properties of self-renewal, and in general, multipotential differentiation capacity. Hematopoietic stem cells (HSCs) have become a stem cell paradigm with their ability both to produce a multiplicity of functionally distinct blood cells throughout life and to reconstitute the hematopoietic system in myeloablated hosts. This picture of hematopoiesis and the central role of stem cells has also now been extended to the concept of leukemic stem cells as critical components in a leukemic cell hierarchy [1]. Recent studies point both to heterogeneity, or subsets, within the normal stem cell compartment [2] and to lineage-restricted progenitors as targets of leukemic stem cell transformation [3]. Such observations have led to the concept of considering stem cells as occupying a functional “state or sub-state” rather than connoting a particular stage of differentiation [4]. This point of view focuses attention on the essential mechanisms that underlie the stem cell state and that potentially overlap between multiple types of stem cells. In the following sections, we briefly review emerging evidence notably from studies of hematopoietic stem cells indicating that the state of “stemness” is a complex outcome of multidimensional interactions between the stem cell and its environment that ultimately and critically impact on the epigenetic status of the HSC.

INTRINSIC REGULATORS OF HSC

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

A large and still not fully characterized repertoire of molecules ranging from cell surface receptors through signal transduction molecules and a myriad of transcription factors are now recognized for their regulatory roles in HSCs. Among these so-called “intrinsic regulators,” transcription factors have attracted much attention given their essential roles in the initial development, expansion, and maintenance of HSCs [5]. Such attention has been reinforced by the understanding that many of these key transcription factors such as mixed-lineage leukemia (MLL), Runt-related transcription factor (AML1), and stem cell leukemia are also major players in leukemogenesis. Moreover, the engineered overexpression in normal HSC of HOXB4 or the variant fusion of HOXA10 and NUP98 among other transcription factors has provided a potent new avenue to enhance the self-renewal of HSC for basic investigations and potentially clinical application [6–9]. Very recently the application of next generation sequencing to genome-wide analysis of hematopoietic transcription factors has provided remarkable new evidence that they operate in a complex combinatorial manner [10, 11]. These hitherto unrecognized multidimensional interactions between transcription factors and their targets provide new insights into the regulatory processes at play in HSC and place new demands on integrated analysis approaches for their study [12]. Such findings have also focused increased attention on the importance of epigenetic regulation as a way of coordinating the expression and activity of such transcription factors in both normal and leukemic stem cells.

EPIGENETICS AND THE HSC STATE

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

Epigenetic Regulation As a Critical Coordinator of Gene Expression Patterns

As described above, numerous studies have identified key transcription factors involved in the self-renewal of HSCs [13], and gene-expression patterns specific to primitive hematopoietic cells were identified [14, 15]. However, given that HSCs can undergo such an extensive spectrum of cell fate decisions from self-renewal to differentiation down myriad specialized pathways, a major question emerges—how on the one hand can a specific gene-expression pattern be maintained consistent with self-renewal and retention of multipotentiality versus gene-expression changes associated with loss of self-renewal and restriction of potential? Studies have shown that epigenetic modifications can change the expression of large sets of genes with changes in the chromatin structures [16], which can influence the accessibility of transcription factors to DNA and alter the transcription profile of cells [17]. The modification of chromatin structures is largely regulated by specific post-translational modifications of histones acting as switches between permissive or repressive chromatin [18]. The modification of histones includes acetylation, methylation, phosphorylation, sumoylation, and ubiquitylation [19]. In general, hyperacetylation of hisone is associated with “open” chromatin, whereas histone deacetylation is associated with “condensation” and heterochromatin formation. Acetylation of histone is catalyzed by histone acetyl transferases including Gcn5-related N-acetyltransferases, MYSTs, and p300/c-AMP response element–binding protein, whereas deacetylation is catalyzed by four distinct families of histone deacetylases (HDACs). Histone is also modified by methylation on arginine or lysine residues. Although arginine methylation is usually associated with gene activation, lysine methylation is related to activation as well as repression depending on the specific residues modified (reviewed by Rice et al. [19]). For example, methylation in the H3K4, H3K36, and H3K79 is related to transcriptional activation, whereas methylation in H3K9, H3K27, and H4K20 is related to repression [20]. The methylation of H3K4 residues is catalyzed by MLL proteins to activate transcription, whereas methylation of H3K27 is catalyzed by polycomb (PcG) repressive complex (PRC)-2,3, which recruits PRC1 to establish repressive chromatin structures [19].

Methylation of CpG in DNA comprises another major category of epigenetic regulation. DNA methylation in promoter regions is associated with transcriptional silencing of genes by promoting the binding of MeCP2 [21], a transcriptional repressor that recruits HDACs to the methylated promoters [22]. DNA methylation is catalyzed by DNA methyltransferases (Dnmt)1 or Dnmt 3a/3b for maintenance or de novo methylaion of DNA, respectively [17]. Thus epigenetic modification and alterations of chromatin structures are important mechanisms that can permit the establishment, maintenance, and changes of “en block” gene expression patterns likely critical to the determination of functional state and cell fates.

Epigenetic Signature for Undifferentiated State of Stem Cells

Major insight into the possible roles of epigenetics in stem cell state has emerged from studies focused on the epigenetic status of undifferentiated pluripotent embryonic stem cells (ESCs). ESCs can be characterized by less-condensed chromatin structures [23, 24] leaving the chromatin more accessible to multiple transcription factors. Moreover, the pluripotent state of ESCs is characterized by “poised,” that is, “primed but held-in-check,” expression of lineage-associated regulatory genes. Such poised gene expression was primarily mediated by a bivalent mode of histone modification; that is, a positive regulatory chromatin mark (H3K4-methylation) is juxtaposed to a repressive chromatin mark (H3K27-trimethylation), where the methylation of H3K27 is catalyzed by PcG group proteins [23–25].

Of note, studies on histone modification of undifferentiated cells showed that chromatin exists in a dynamic equilibrium between open and “closed” states, maintaining “fluidity” of chromatin [26], and that these dynamic changes in the chromatin states may be mediated by nucleosome remodeling and histone acetylation [27]. Moreover, efficient acquisition of pluripotent state from somatic cells was dependent on the open chromatin state maintained by chromatin remodeling factor such as chd1 [28], and the cell reprogramming process was facilitated by chemical treatment that can cause decondensation of the chromatin structure [29, 30]. Thus poised expression and dynamic remodeling of chromatin comprise characteristics of pluripotent stem cells.

Epigenetic Signature for HSCs

Growing evidence also point to a key role for epigenetic “signatures” in relation to HSCs and hematopoietic differentiation [19, 31]. For example, hematopoietic progenitor cells exhibit a promiscuous, low-level expression of lineage-specific genes before commitment [32, 33]. In addition, hematopoietic differentiation correlates to a stepwise decrease in the transcriptional accessibility of multilineage-affiliated genes [32, 34], and changes in the expression of lineage-specifying genes in hematopoietic progenitors were correlated with changes in chromatin structures in the promoter regions during differentiation [35, 36]. Analysis of lineage-associated genes in various stages of murine hematopoietic progenitors also revealed concerted epigenetic modifications of the selected hematopoietic genes by DNA methylation and histone modification [37]. Moreover, recent genome-wide analyses of hematopoietic progenitors and lineage-specific progenitors using comprehensive high-throughput array-based relative methylation revealed that lineage-specific differentiation is associated with modulation of DNA methylation [38]. Interestingly, differential DNA methylation with hematopoietic differentiation was more strongly correlated with DNA methylation in the CpG shore (regions within 2 kb of island) than in CpG islands. In addition, myeloid commitment involved less global DNA methylation than lymphoid commitment, which was supported by the finding for a myeloid shift of progenitors following methyltransferase inhibition [38]. Similar hypomethylation of myeloid cells was observed in a study using human hematopoietic progenitor cells, wherein distinct methylation patterns were also observed between young- and old-age progenitor cells [39]. These results show that DNA methylation is involved in the regulation of lineage-specific differentiation as well as aging-associated changes of hematopoietic progenitors.

Recently, one of us (I.-H. Oh) analyzed the genome-wide DNA methylation of undifferentiated human hematopoietic cells (CD34+) in comparison to differentiated cells (CD34−) and showed that undifferentiated cells were characterized by undermethylation at the transcription start site of the promoter region (a so call dip) and overmethylation of flanking regions [40]. Interestingly, the regions of undermethylation dip in CD34+ cells were significantly enriched with genes encoding nuclear proteins for chromatin remodeling, suggesting that the genes involved in the dynamic changes of chromatin structures are primed in the undifferentiated status. Moreover, we found that undifferentiated human and murine hematopoietic cells displayed less-condensed chromatin structures and exhibited a higher rate of histone acetylation in pulse-chase experiments, indicating that undifferentiated cells are in a state of higher turn-over of chromatin structures than differentiated cells [40]. This is highly reminiscent of the observation in ESCs that exhibit hyperdynamic chromatin proteins in a pluripotent state, but these proteins were immobilized on chromatin in the differentiated state [41]. Thus, it is possible that the undifferentiated state of hematopoietic cells can be characterized by a higher turn-over rate of epigenetic modifications to maintain dynamic state of chromatins, compared with more differentiated cells (schematically shown in Fig. 1).

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Figure 1. Schematic illustration of the model for the epigenetic integration of hematopoietic stem cell (HSC) state. Undifferentiated hematopoietic cells (A) have dynamic chromatin structures with high turn-over rate of epigenetic modification, being permissive to alterations in chromatin structures (as represented by multiple arrows in A). Treatment of undifferentiated cells with epigenetic chemicals (AZA/TSA) further enhance self-renewal potential of hematopoietic progenitors (B), whereas similar treatment of mature cells (C) leads to limited dedifferentiaiton (D) and apoptosis. Therefore, the undifferentiated state of HSCs can be represented by epigenetic plasticity and multilineage potential. In addition, hematopoietic transcription factors and microenvironmental regulation in the stem cell niche regulate tissue-specific hematopoietic functions of HSCs. Thus, the stem cell states of HSCs are determined by multidimensional integration of tissue-specific hematopoietic functions and the epigenetic plasticity of undifferentiated cells. Abbreviations: AZA, 5-azacytidine; TSA, trichostatin A.

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Functional Impact of Epigenetic Signature

The apparent unique epigenetic status of undifferentiated hematopoietic cells suggests important roles of epigenetic modifications in conferring HSC properties. In support of this view, lack of functional Dnmts was shown to cause defective self-renewal of HSCs. Specifically, conditional disruption of Dnmt3a and 3b, two enzymes responsible for de novo DNA methylation, did not overtly affect later hematopoietic progenitors or more primitive cells capable of transient lymphomyeloid engraftment. However, major defects were apparent in the long-term reconstitution of HSCs, thus indicating that de novo DNA methylation is required for self-renewal of HSCs [42]. Similarly, conditional disruption of Dnmt1, the enzyme for maintenance methylation of DNA, led to loss of HSC self-renewal and defective production of mature bone marrow (BM) cells over multiple lineages [43]. Interestingly, another study using a hypomorphic Dnmt1 allele revealed somewhat different outcomes with defective hematopoiesis both in myeloablative and nonmyeloablative conditions [44], whereas complete deletion of Dnmt1 led to a defective repopulation only in the “stressed” (transplantation into conditioned recipient) but not in the “steady” condition [43]. Moreover, donor cells from hypomorphic Dnmt1 exhibited a total lack of B-lymphopoiesis with a moderate decrease of myeloid reconstitution, whereas HSCs from Dnmt1-deleted mice exhibited profound decrease in myeloid potential but retained T- and B-lymphoid repopulating potential. In addition, the hypomorphic Dnmt1 allele did not show any defect in competitive homing into BMs, whereas deletion of Dnmt1 led to a defect in homing of HSCs exhibiting lower retention of HSC in the niche. The reasons for these differences in functional outcomes remain unclear, but it remains to be determined whether distinct biological impacts can be caused with respect to their differences in DNA methylation levels. Interestingly, DNA hypomethylation was also associated with defects in the self-renewal of leukemic stem cells with the Dnmt1 hypomorphic allele manifesting defective development of B-lymphoid leukemia and decreased leukemic stem cell self-renewal [44]. Taken together, these studies point to a critical role of DNA methylation in normal and malignant HSCs for regulation of self-renewal and hematopoiesis.

Similar to the influence of DNA methylation changes, histone modifications also exert diverse effects on HSC function. Some important examples include the observed loss of HSC self-renewal and HSC exhaustion on disruption of BMI1, a PcG protein in PRC1 [45]. Similarly, loss of long-term repopulating HSCs was also observed after disruption of Mph1/Rae28, another PRC1 complex protein [46]. In contrast, loss of Ring1b or mice with hypomorphic mutations of Eed or Suz12, the components of the PRC2 complex, exhibited upregulated hematopoietic activities, indicating a crucial interplay between histone modifications and HSC regulation (reviewed by Konuma et al. [47]).

Further pointing the key roles for DNA methylation and histone modification on HSCs, series of studies have shown that treatment of hematopoietic progenitors with chemicals inhibiting DNA methylation and histone deacetylation during in vitro culture was associated with higher maintenance of the undifferentiated state and increased expansion of hematopoietic progenitors [48–50]. Moreover, in vivo administration of the epigenetic inhibitors trichostatin A (TSA, inhibitor of HDAC) and 5-azacytidine (AZA, inhibitor of Dnmt) resulted in enhanced self-renewal of transplanted HSCs [40]. Together, these studies suggest that tethering of chromatin into a “less dense” state can indeed promote higher maintenance of undifferentiated status and self-renewal of HSCs. Interestingly, the response of hematopoietic cells to such epigenetic modifiers was dependent on the degrees of maturation of the target hematopoietic cells. For example, when more mature (LSK or Lin+) hematopoietic cell populations were similarly treated with TSA or AZA, limited dedifferentiation was observed but was accompanied by extensive levels of apoptosis, the extent of which was inversely correlated to the degrees of undifferentiation [40]. This raises an interesting speculation that the more undifferentiated the cells are, the greater is their potential flexibility to epigenetic alterations of chromatin structures, and that such epigenetic flexibility is correlated to the hierarchy of undifferentiated state (model in Fig. 1).

MICROENVIRONMENTAL REGULATION OF HSCs

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

Stem Cell Niche in BM

Although the precise transcriptional program operative and epigenetic modifications exert crucial regulatory influences on the HSC-state, growing evidence also point to the important regulatory role of the HSC microenvironment, or niche, in the BM. The microenvironmental regulation of HSCs mostly occurs in a specialized architecture of BMs, referred to as the stem cell niche, where the majority of HSCs reside and are regulated for self-renewal, quiescence, survival, and differentiation (reviewed by Oh [51]).

Current evidence has pointed to the existence of two types of niches in the BM, an endosteal osteoblastic and a vascular/perisinusoidal niche. The vascular niche is composed of reticular cells around the sinusoid or a subendothelial (adventitial) layer of sinusoidal walls, projecting a reticular process in close contact with HSCs in human BM [52]. Recent studies have indicated that sinusoidal endothelial cells (SECs) also constitute an endothelial niche, that is, infusion of endothelial progenitor cells was associated with higher recoveries of HSCs [53] and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) signaling during the recovery of BM prevented not only the regeneration of SECs but also the reconstitution of transplanted HSCs [54]. Although the osteoblastic and vascular niches share a common cellular origin as well as common growth factors, evidence also shows that HSCs are distinctively localized in these two types of niches depending on the physiological conditions of BMs [55, 56] suggesting that these two niches might have distinct functions for HSCs (concisely reviewed in [51]).

Microenvironmental Crosstalk in the Stem Cell Niche

A large number of potential regulators have been identified and found to share some common modes of action in triggering of crosstalk between the niche and HSCs. Notable among these are crosstalk between jagged-1/notch signaling and convergence of signals to the chemokine (C-X-C motif) ligand 12/C-X-C chemokine receptor 4 (CXCL12/CXCR4) signaling axis (schematically shown in Fig. 2).

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Figure 2. Microenvironmental regulation of hematopoietic stem cells (HSCs) in multiple niches of bone marrow. The microenvironmental regulation in niche can be categorized into several axis of crosstalk. First, extrinsic factors such as PTH signaling or canonical wnt/β-catenin induce jagged-1 in the stromal niche to activate notch in HSCs, whereas OPN suppresses the induction of jagged-1. Thus jagged-1/notch axis represents one of conserved elements of crosstalk in the stem cell niche (yellow area). Second, several signals including PTH or 5-FU induce the expression of CXCL-12, whereas G-CSF or sympathetic nerve system downregulates CXCL-12 to release HSCs, indicating that CXCL-12/CXCR4 axis represents another axis of crosstalk (blue area). Third, growth factors such as angiopoietin-1, TPO, or IL-10 exert their effects in conjunction with stroma in the bone marrow niche (green area). Finally, intrinsic molecules such as Nf2, Rb, FANCB, RAR-γ, Bis, or Sbd influences niche activities in a yet poorly defined manner but modulate hematopoietic activity in a stroma-dependent manner (white area). Notably, Jagged-1 or CXCL-12 axis is also similarly shared by cells in the vascular niche (reticular cells or SEC; marked by blue line arrows). (+) represent upregulation, (−), downregulation, curved arrows represent self-renewal of HSCs. Abbreviations: CXCL, chemokine (C-X-C motif) ligand; CXCR, C-X-C chemokine receptor 4; FU, 5-fluorouracil; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; OPN, osteopontin; PTH, parathyroid hormone; SEC, sinusoidal endothelial cell; RARγ, retinoic acid γ; TPO, thrombopoietin.

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Jagged-1/notch Axis in the Niche

Parathyroid hormone (PTH)/PTH-related protein [57] has been shown to induce jagged-1 expression in osteoblasts being associated with increased HSC numbers and hematopoietic activity [57]. Wnt/β-catenin is also linked to jagged-1/notch axis in stroma [58]. Of note, our recent work has shown that distinct biological outcomes can be caused by wnt/β-catenin signals depending on the target site of their activation. Thus direct stabilization of β-catenin in HSCs resulted in the loss of their repopulating activity, whereas stabilization of β-catenin in the stroma led to enhanced self-renewal of HSCs in a contact-dependent manner [58]. Stromal activation of wnt/β-catenin signaling leads to induction of notch ligand and exerts a stimulatory effect on HSC in a notch signal-dependent manner, revealing a functional crosstalk in the stem cell niche [58]. Moreover, direct intrafemoral injection of β-catenin-activated MSCs stimulated self-renewal of transplanted HSCs several fold higher than the HSCs injected along with naïve MSCs [59] (further reviewed by Oh [60]). Osteopontin (OPN) is another signal implicated in notch regulatory axis. In an OPN-null microenvironment, the number of HSCs is increased in association with elevated stromal Jagged-1 and Angiopoietin-1 expression [61]. Of note, a study showed that endothelial cells, in addition to osteoblast, use the notch axis, that is, adenoviral gene E4–open reading frame–immortalized endothelial cells supported the expansion of the long-term repopulating HSCs in a manner dependent on notch signal activation in HSCs [62].

CXCL-12/CXCR4 Signaling

As described, reticular cells expressing high levels of CXCL-12 (CXCL-12 abundant reticular cells) are in contact with 90% of HSCs and its production is increased in the presence of DNA damaging agents (irradiation, 5-fluorouracil, cyclophosphamide) or by PTH activation [63]. In addition, recent studies in mice with defective nerve conduction showed that HSC mobilization by granulocyte colony-stimulating factor is dependent on the intact adrenergic nerve system and that norepinephrine downregulates osteoblast expression of CXCL-12 [64]. Thus, the CXCL-12/CXCR4 axis may serve as an important modulator of niche activity and, hence, HSCs, in response to environmental conditions or stress.

Other Growth Factors

In addition to crosstalks described above, a growing number of hematopoietic growth factors are being identified as microenvironmental factors. For example, thrombopoietin is produced in osteoblasts that are in close contact with long-term HSCs [65]. Similarly, angiopoietin-1 was shown to be expressed in the osteoblastic niche as well as in the reticular cells in the vascular niche of BM [52]. Of note, our study showed that interleukin 10, a pleiotrophic cytokine regulating immune reaction, also functions as a growth factor promoting self-renewal of murine HSCs, and its production is induced in the endosteal osteoblast in response to the radiation stress on BM [66].

Intrinsic Molecules That Control the HSC Niche

In addition to extrinsic growth factors playing a role in the HSC niche, recent studies are beginning to identify intrinsic molecules that can regulate the activity or integrity of the hematopoietic niche. For example, in mice with a disruption in Nf2/merlin, HSC frequencies are increased and shifted into the circulation with an associated increase in trabecular bone mass and stromal cell numbers, as well as vascularity and VEGF levels [67]. Conversely, our recent study showed that targeted disruption of bis, the gene encoding antiapoptotic protein interacting with Bcl-2, led to loss of HSCs with selective deterioration of the vascular niche accompanied by loss of CXCL12 expressing stromal cells in BM but without affecting the osteoblastic niche [68]. Similarly, loss of the murine homolog of FANCB led to microenvironmental defects mimicking the hematological signs of Fanconi anemia, that could be rescued by the adoptive transfer of wild-type MSCs [69].

Of note, alteration of the niche can also lead to a pathological microenvironment leading to abnormal hematopoiesis. For example, mice deficient in retinoic acid γ develop a myeloproliferative syndrome in a microenvironment-dependent manner [70]. Similarly, the disruption of Rb causes a defective interaction in hematopoietic cells with the microenvironment leading to the myeloproliferative disease of BMs and mobilization of primitive cells into extramedullary organs [71]. More recently, deletion of Dicer1 specifically from the osteoprogenitor cells reduced expression of sbd gene, which led to BM dysfunction and myelodysplasia due to stromal dysfunction [72]. Taken together, these findings now implicate the microenvironment as a new entity that has the ability to mediate the regulation of the hematopoietic activity of HSCs during physiological as well as abnormal disease conditions.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

Hematopoietic stem cells can be considered to occupy a unique functional and molecular state represented by maintenance of multilineage differentiation potential and self-renewal capacity. As reviewed, the undifferentiated state of HSCs is maintained by unique epigenetic signatures including epigenetic plasticity and bivalent modifications, akin to signatures of pluripotent stem cells. However, the unique tissue-specific functions of HSCs are also regulated by hematopoietic transcription factors and microenvironmental factors being integrated into HSC identity. Emerging evidence also suggest functional connection between extrinsic growth factors and epigenetic modifications and of extrinsic factors and transcription factors. Thus HSCs exist and function by virtue of multidimensional regulatory mechanisms to simultaneously carry out the two opposing properties of HSCs, that is, maintenance of undifferentiated state analogous to pluripotent stem cells but execution of tissue-specific hematopoietic functions. Thus the identify of stemness in HSCs should be considered as a net interplay of those genetic, epigenetic, and microenvironmental elements integrated together, rather than a master regulatory force by limited regulatory forces (schematically drawn in Fig. 1). It is also likely that such interplay of multiple regulatory forces as a “determinant” of cell fate could be also extrapolated toward diverse spectra of tissue-specific stem cells. Further studies on the interplay of such regulatory mechanism will shed the light into stemness and regenerative function of tissue-specific stem cells.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES

This study was supported by a grant from Korea Science and Engineering Foundation (KOSEF; Stem cell research project, 2011-0019352) and by a Terry Fox Foundation Program Project Award (to R.K.H.).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. INTRINSIC REGULATORS OF HSC
  5. EPIGENETICS AND THE HSC STATE
  6. MICROENVIRONMENTAL REGULATION OF HSCs
  7. CONCLUSION
  8. Acknowledgements
  9. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
  10. REFERENCES