Minireview: Nuclear Receptors, Hematopoiesis, and Stem Cells

Abstract

Nuclear receptors (NRs) regulate a panoply of biological processes, including the function and development of cells within the hematopoietic and immune system, such as erythrocytes, monocytes, and lymphocytes. Significantly less is known regarding the function of NRs in regulating the fate of hematopoietic stem cells (HSCs), the self-renewing, pluripotent cells that give rise to the entirety of the blood and immune systems throughout the lifetime of an individual. Several recent studies suggest, either directly or indirectly, a role for members of the NR family in regulating the differentiation and self-renewal of HSCs, embryonic stem cells, and induced pluripotent stem cells. Herein, we review in detail the function of specific NRs in controlling HSC and other stem cell fate and propose a framework through which these observations can be translated into therapeutic amplification of HSCs for clinical purposes.

Nuclear receptors regulate hematopoietic and embryonic stem cell fate determinations and represent attractive targets for pharmacologic modulation to augment cellular therapy and tissue regeneration.

Introduction to Hematopoiesis and HSC Regulation

Hematopoietic stem cells (HSCs) possess the unique capacity to self-renew and give rise to the entirety of the blood and immune systems throughout the lifetime of an individual (Fig. 1) (1,2). Unlike other tissue-specific stem cells, hematopoietic stem and progenitor cells can be readily isolated to near purity using immunohistochemical staining and fluorescence activated cell sorting and characterized via well-established functional assays (Fig. 1). For example, murine bone marrow (BM) HSCs are lineage negative, c-kit⁺, sca-1⁺, and lack CD34 expression (34⁻KLS cells), and BM HSC numbers can be estimated via competitive transplantation of limiting doses of donor BM 34⁻KLS cells into lethally irradiated congenic recipient mice (competitive repopulating assay) (1,2,3,4). HSC self-renewal is regulated by both cell-intrinsic and -extrinsic pathways but the mechanisms controlling this process remain incompletely understood (1,2,3,4,5,6). Several transcription factors, including HoxB4, β-catenin, HES1, and GFI-1, are known to regulate the HSC self-renewal and differentiation program (Fig. 2) (3,4,5,6). Several of these targets are thought to be ligand inducible. For example, β-catenin signaling can be activated via treatment of murine HSCs with soluble Wnt3a, resulting in HSC expansion in culture (3). HES1 signaling can be also induced via binding of a Notch ligand (e.g. Jagged or Delta1) to the Notch receptor on HSCs, resulting in HSC self-renewal (5,7). Recently, treatment of murine HSCs with prostaglandin E2 (8) or angiopoietin-like protein-2 or -3 has been shown to induce significant expansions of repopulating HSCs in culture (9). Less is known regarding the contribution of nuclear receptors (NRs), ligand-inducible transcription factors, in regulating HSC fate determinations (10,11). However, given the contribution of NRs to a variety of biological processes and the availability of pharmacological ligands to modulate NR activities, further study of NRs in hematopoiesis is merited. Herein, we summarize the established functions of NRs in regulating hematopoiesis and HSC fate and highlight how manipulation of these receptors with small molecule ligands may have clinical utility in hematopoietic cell expansion and augmentation of hematopoiesis in vivo (Table 1).

Figure 1.

Overview of the hematopoietic hierarchy. The spectrum of hematopoietic stem and progenitor cells and their progeny are represented along with the phenotype and functional assays used to characterize the stem and progenitor cell pool. LTHSC, Long-term repopulating hematopoietic stem cell; STHSC, short-term repopulating hematopoietic stem cell; MPP, multipotent progenitor cell; CMP, common myeloid progenitor cell; MEP, megakaryocyte-erythroid progenitor cell; GMP, granulocyte monocyte progenitor cell; CLP, common lymphoid progenitor cell; RBC, red blood cell; 34-KLS, CD34- c-kit+lineage- sca-1+ cells; CRU, competitive repopulating unit assay; CFU-Spleen, colony forming unit-spleen assay; CFC, colony-forming cell assay, d 14.

Figure 2.

Schematic overview of major HSC self-renewal pathways. The most well-characterized signaling pathways and transcription factors involved in regulating HSC self-renewal are shown. BMP, Bone morphogenetic protein; NICD, notch intracellular domain; RBPJ, recombinant signal binding protein; LEF, lymphoid enhancer binding protein; GFI-1, growth factor independent 1; HOX, homeobox proteins.

Table 1.

NRs that regulate hematopoiesis and stem cell fate hematopoiesis

Receptor	Function	References
RARα	Myeloid differentiation	20,21,27,28,29,30,33
	HSC differentiation (human)	27,34
RARγ	HSC self-renewal	10,11
RXR	HSC differentiation	34
	Inhibits erythroid differentiation	34,35
TRα	Erythroid differentiation	38,40,41,42
GR	Erythroid progenitor expansion	43,45,46,47,48,50
	Stress erythropoiesis	43
ERβ	Inhibition of B lymphopoiesis	51,52,53,54,55,56
	Inhibition of early myelopoiesis	51,52
AR	Erythroid progenitor expansion	60,63
	Inhibition of B lymphopoiesis	65
VDR	Monocyte differentiation	69
	Th1 immune response	66,70
PPARγ	Myeloid differentiation	34
	Inhibition of erythoid differentiation	75
Nur77 + Nor1	HSC differentiation	79
ES cell differentiation and iPS
Esrrb	Represses ES cell differentiation	86,89
SF-1	Maintains ES cell pluripotency	86,92,93
DAX1	Repression of ES cell differentiation	86,95,96
GCNF	ES cell differentiation	86,97,98,99,100
Esrrb	Induced pluripotency (iPS) in adult cells	103

Retinoid Receptors

Retinoic acid (RA) is a vitamin A derivative with well-described effects on development and cellular differentiation (12,13,14). There are three isoforms of the retinoic acid receptor (RAR) (α, γ, β), which act as ligand-inducible transcription factors with distinct functions (15,16,17). The RARs are the most well-characterized NRs with regard to regulation of hematopoiesis and hematopoietic stem cell (HSC) function (10,18,19). This field of study was catalyzed by the observations of Breitman et al. (20,21) that incubation with all-trans retinoic acid (ATRA) caused the differentiation of both a human promyelocytic leukemia cell line (HL-60) and primary human promyelocytic cells in culture. Subsequently, it was shown that acute promyelocytic leukemia cells carry a t15;17(q21-q11-22) translocation, resulting in the expression of a promyelocytic leukemia (PML)-RARα fusion protein that functions as a dominant-negative inhibitor of both promyelocytic leukemia and RARα at their respective target genes (22,23,24). Treatment of patients with ATRA, combined with chemotherapy, induces complete remission of acute promyelocytic leukemia and is curative in many cases (25,26).

The role of retinoid signaling in regulating normal hematopoietic progenitor cell differentiation is also well established. ATRA stimulates the proliferation of myeloid progenitors (27) and induces the granulocytic differentiation of myeloid progenitors (28), and introduction of a dominant-negative RARα construct into a hematopoietic progenitor cell line suppresses neutrophil and monocyte development (29). Activation of RARα with ATRA has also been shown to inhibit the proliferation of human embryonic hematopoietic progenitor cells and adult cobblestone-area forming cells in culture and promote the apoptosis of human CD34⁺ cells (30,31,32). Although RARα is not required for granulocytic differentiation to occur (33), this receptor clearly plays an important role in inducing hematopoietic progenitor cell differentiation.

In addition to promoting the differentiation of myeloid progenitor cells, RARs regulate both murine and human HSC differentiation (10,11,27). Treatment of murine c-kit⁺sca-1⁺lin⁻ (KSL) stem/progenitor cells in culture with ATRA has been shown to enhance the maintenance of murine repopulating HSCs in vitro (10). Purton et al. (11) further demonstrated that ATRA-mediated maintenance of murine HSCs in culture was dependent upon RARγ and independent of RARα, suggesting that RARγ is an important positive regulator of murine HSC self-renewal (Fig. 2). Consistent with these findings, the authors also showed that RARγ−/− mice contain significantly less BM HSCs compared with wild-type mice (11). Interestingly, Chute et al. (27) reported that pharmacological inhibition of the enzyme, aldehyde dehydrogenase 1, which is required for the intracellular production of retinoids, caused a 3- to 4-fold expansion of human HSCs in culture. These results suggested perhaps opposing effects of retinoids in regulating HSC fate in mice and humans or that inhibition of aldehyde dehydrogenase 1 modified HSC fate via a mechanism independent of the retinoid receptors (27).

The role of retinoic X receptor (RXR) in regulating HSC fate has also recently been addressed (34). It has been previously shown that RXR functions as a negative regulator of erythropoiesis (35) but Safi et al. (34) demonstrated that human HSCs could be maintained in culture via the addition of a small molecule, LG1506, which antagonized RXR:RAR signaling. LG1506 was shown to bind RXRs, the obligate partners of RARs, facilitating an allosteric event that resulted in inhibition of RAR, within the RXR:RAR heterodimer. Although deletion of RXRα was not associated with any hematopoietic defects in mice (36), more global inhibition of all three RXRs, as was accomplished pharmacologically, inhibited the differentiation of human HSCs in culture (34). Taken together, these data suggest that pharmacological antagonism of retinoid signaling inhibited human HSC differentiation and enhanced the maintenance of human HSCs in culture. It is plausible that signaling via RAR and RXR mediate distinct differentiation events in mice and humans to explain the observations by Purton et al. (10,11) and Chute et al. (27) and Safi et al. (34). Nonetheless, it is clear that RAR and RXR have important and diverse functions in regulating murine and human HSC self-renewal and differentiation events. As such, these receptors represent excellent targets for therapeutic manipulation to expand HSCs for clinical purposes.

Thyroid Hormone Receptor (TR)

TRα is a member of the class II NRs (37). In the absence of ligand, TRs bind to specific thyroid response elements (TREs) within target genes and, as a consequence of their ability to interact with NR corepressors, they actively suppress gene transcription (38,39). Upon binding an agonist such as thyroid hormone (T₃), the receptor undergoes a conformational change that facilitates the dissociation of corepressors and binding of coactivators; the binding of coactivators results in transcriptional activation (38). TRα is expressed by hematopoietic and erythroid progenitors (40), and hypothyroidism is clinically accompanied by a reduced red blood cell mass and normocytic anemia (41). The avian erythroblastosis virus (AEV) oncoprotein, v-ErbA, represents a mutated, oncogenic form of TRα (c-ErbA/TRα). The addition of T₃ activates the cErbA/TRα receptor in erythroblasts, blocks self-renewal, and induces synchronous, terminal differentiation in culture (38). Conversely, vErbA cooperates with ligand-activated c-kit receptor to induce the self-renewal and arrest of differentiation of primary avian erythroblasts, resulting in a fatal erythroleukemia (38). Taken together, Bauer et al. (38) demonstrated that cErb/TRα represents a ligand-operated molecular switch, regulating the balance between erythroblast self-renewal and differentiation.

Recently, Kendrick et al. (42) verified the essential function of TRα in regulating erythropoiesis by characterizing the phenotype of TRα−/− mice. TRα mice had significantly reduced numbers of erythroid progenitor cells in the fetal liver, decreased hematocrits as adults, and a diminished erythroid stress response to hemolytic anemia (42). Although no defect was identified in HSC or progenitor cell numbers in the adult TRα−/− mice, these studies confirmed the essential function of TRα in regulating erythropoiesis both during development and in the adult.

Glucocorticoid Receptor (GR)

The importance of the GR in regulating erythropoiesis has long been inferred from the clinical observation that patients who lack glucocorticoid production (Addison’s disease) have a normocytic anemia (43,44). Similarly, patients with Cushing’s syndrome, in which there are excess circulating glucocorticoids, have elevated hemoglobin and hematocrit levels (43,44). Experimentally, Golde et al. (45) first demonstrated that dexamethasone promotes the generation of murine erythroid colony-forming cells (45), and glucocorticoids also enhance erythroid progenitor cell proliferation in response to limiting amounts of erythropoietin (46). The GR is expressed by erythroid progenitor cells, and activation of GR with dexamethasone induces the proliferation and expansion of erythroid progenitors while maintaining their colony-forming capacity and delaying the terminal differentiation of erythrocytes (47). Importantly, these effects of GR require cooperation with the erythropoietin receptor and c-kit activation in order for erythroid progenitor expansion to occur (47). It has also been shown that this expansion of erythroid progenitors requires the DNA-binding and transactivation function of the GR (48,49). Interestingly, Stellaci et al. (50) recently demonstrated GR-mediated inhibition of terminal erythroid differentiation is mediated via interference with erythropoietin-mediated signaling.

Importantly, GR−/− mice are not viable, but examination of erythropoiesis in GR−/− embryos demonstrates no obvious defect in erythropoiesis (43). However, studies of GR dim/dim mice vs. wild-type mice demonstrate an essential role for GR in the stress erythroid response to blood loss or hemolysis (43). GR dim/dim mice showed no increase in colony-forming unit-erythroid (CFU-E) in response to hemolysis and no increase in red blood cell count, hemoglobin, or hematocrit in response to hypoxia, whereas wild-type mice demonstrated strong erythroid responses to both stresses (43). Taken together, these data illustrate an important function of GR in regulating the erythroid progenitor response to stress. No obvious alterations in HSC content or function were observed in GR dim/dim mice compared with wild-type mice, suggesting that GR does not play an essential role in regulating HSC fate.

Estrogen Receptor (ER)

It has long been recognized that women have significantly increased risk of autoimmune diseases compared with men (51). However, a mechanistic link between estrogen receptor activation and immune function has only recently been elucidated. The loss of estrogen in ovariectomized mice is associated with splenomegaly, increased BM CFU-GEMM, BFU-E, and B lymphocytes (51,52). Conversely, administration of exogenous estrogen decreases B lymphopoiesis (51,53) and, surprisingly, was shown to inhibit B lymphoid and myeloid differentiation of BM HSCs (54,55). Estrogen exerts its effects through ERα and ERβ (51). ERα and ERβ are both expressed by microenvironment cells in the BM, but ERα−/− mice have a normal hematopoietic profile with the exception of a reduction in BM B lymphocyte subsets (51,56). Moreover, administration of exogenous estrogen to ERα−/− mice causes a decrease in B lymphopoiesis (51,56), suggesting that estrogen effects on hematopoietic progenitors may be mediated by ERβ.

ERβ−/− mice have also been examined for evidence of long-term hematopoietic defects (51). By age 1.5 yr, ERβ−/− mice have marked splenomegaly, BM myeloid hyperplasia, lymphadenopathy, and leukocyte infiltration in the lungs and liver, consistent with a lymphoid blast crisis of chronic myelogenous leukemia (51). Taken together, these data suggest that ERβ is an important negative regulator of hematopoietic progenitor cells (51). In light of these observations, it has been suggested that ERβ agonists may be useful in the treatment of patients with acute and chronic leukemia (51,57).

Androgen Receptor (AR)

The AR is expressed in all reproductive tissues in men, as well as muscle, skin, bone, and hematopoietic cells (58). Healthy men maintain higher steady-state levels of hemoglobin and red blood cell mass compared with healthy women. During andropause, aging males can develop a normocytic anemia that is associated with a decline in free testosterone levels and can be corrected via testosterone administration (59). However, the mechanisms through which androgens stimulate erythropoiesis are poorly understood (60). Early animal studies demonstrated that several testosterone derivatives could cause an increase in erythropoietin production in the kidneys (61) and the erythropoietic effects of testosterone administration in mice could be abolished by nephrectomy (62). However, more recent studies have not confirmed that the effects of androgens on erythropoiesis are erythropoietin dependent (60). Alternately, BM erythroid progenitor cells express AR, and the addition of androgens to culture of primary erythroid progenitor cells results in a significant expansion of erythroid progenitors without substantial terminal differentiation (63). In the same study, it was shown that the addition of T₃ to erythroid progenitor cultures caused terminal differentiation of the erythroid progenitors. Taken together, these data demonstrate that the expansion of erythroid progenitors and their terminal differentiation are regulated in a coordinated manner by AR and TR activation (63).

Homozygous deletion of AR in male mice is grossly associated with a female phenotype and a significant reduction in trabecular bone but without formal description of effects on erythropoiesis in these animals (64). An unexpected finding in AR knockout mice was a significant expansion of the B cell pool and splenic enlargement caused by the expansion of B progenitor cells in the BM (65). These data indicate that AR functions in hematopoiesis beyond its role in promoting erythropoiesis, perhaps as a negative regulator of B lymphopoiesis. There is no information as to the function of AR in regulating HSC function or content in vitro or in vivo, but AR−/− mice have normocellular BM, suggesting that AR is not an essential regulator of hematopoiesis (64).

Vitamin D Receptor (VDR)

The VDR is a transcription factor that mediates the actions of its cognate ligand, 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃], in regulating calcium homeostasis (66). However, VDR is widely expressed in many tissues including hematopoietic progenitor cells (67,68) and culture of human CD34+ hematopoietic progenitor cells with 1,25-(OH)₂D₃ induces massive monocyte commitment in vitro via activation of HoxA10 and MafB, a master regulator of monocyte differentiation (69). Independently, it was shown that 1,25-(OH)₂D₃ inhibits the proliferation and cytokine production of T cells in culture (66,70). Interestingly, BM HSCs from VDR knockout mice can be induced to generate differentiated monocytes, but these mice have an impaired Th1 cell response (66). Taken together, these results demonstrate that VDR is not essential for monocytic differentiation of HSCs but may be required for the normal Th1 immune response (66).

Peroxisome Proliferator-Activated Receptor (PPAR)

PPARγ is an NR that has deterministic function in regulating adipogenesis and metabolism (71). Humans with diminished PPARγ activity have features of insulin resistance, dyslipidemia, and hypertension, and rosiglitazone, a PPARγ agonist, is used to augment insulin sensitivity and lower blood glucose levels in patients with type II diabetes mellitus (72,73,74). PPARγ ligands, troglitazone and pioglitazone, have been shown to suppress the proliferation and delay the maturation of primary erythroid progenitor cells (75). More recently, Prost et al. (76) reported the unexpected finding that human and simian immunodeficiency viruses inhibited hematopoietic progenitor cell growth via induction of an accessory viral protein, negative factor, and the actions of negative factor were dependent upon the presence of PPARγ in the hematopoietic progenitor cells. Moreover, the authors showed that treatment of mice or macaque monkeys with rosiglitazone × 15 d in vivo caused a significant decrease in the number of BM colony-forming cells (CFCs) recovered compared with untreated control animals (76). The inhibitory actions of PPARγ on hematopoietic progenitor cell growth were demonstrated to be mediated by inhibition of signal transducer and activator of transcription 5 signaling in the target cells (76).

More recently, Safi et al. (34) studied the activity of several PPAR agonists on the proliferation and expansion of human CD34⁺CD38⁻lin⁻ HSCs in culture. The addition of clofibrate, a PPARα agonist, to human HSCs had no effect on total cell, CD34⁺, or CD34⁺CD38⁻ progenitor cell expansion or CFC content in liquid suspension with thrombopoietin, stem cell factor, and Flt-3 ligand (34). Similarly, the addition of carbaprostacyclin, a PPARδ agonist, also had no effect on human stem/progenitor cell content in culture. Conversely, the addition of rosiglitazone, a PPARγ agonist, caused a decline in primitive CD34⁺CD38⁻ cells and a significant increase in production of committed CFCs in culture compared with cytokines alone. Taken together, these results indicate that activation of PPARγ induces the myeloid differentiation of human HSCs rather than HSC self-renewal. It remains to be determined whether PPARγ is essential for myeloid maturation of HSCs because homozygous deletion of PPARγ is embryonic lethal in mice, and the hematopoietic phenotype of heterozygous PPARγ+/− mice has not been described (77,78). Because PPARγ is a heterodimeric partner of RXR and studies by Safi et al. demonstrated that antagonism of RXR blocked the differentiation of HSCs in response to cytokines, it will be important to verify whether RXR mediates actions on hematopoiesis via PPARγ signaling events. Preliminary studies by Safi et al. (34) suggested that PPARγ was not involved in mediating effects of RXR on HSC differentiation.

Orphan Receptors

The homologous orphan nuclear receptors, Nur77 and Nor-1, have been shown to promote the apoptosis of T and B cells (79,80,81), the apoptosis of nonhematopoietic epithelial cells in response to chemotherapy, and the proliferation of epithelial cells in response to growth factors (79,80,81). Lee et al. (82) showed that deletion of Nur77 alone caused minimal T cell functional defects, and Ponnio et al. (83) reported that deletion of Nor-1 caused defective development of the inner ear. However, mice that are deficient in both Nur77 and Nor-1 develop a marked expansion of phenotypic long-term HSCs with a block in differentiation, leading to acute myelogenous leukemia and early death (79). The authors also demonstrated that Nur77−/−;Nor1−/− mice displayed decreased expression of JunB and c-Jun, which are involved in the normal differentiation of myeloid progenitor cells (79,84,85). Taken together, these results suggest a role for Nur77 and Nor-1 as positive regulators of HSC differentiation that perhaps mediate effects via JunB and c-Jun signaling (79). It remains to be determined whether genetic enforcement or pharmacological activation of Nur77 or Nor-1 signaling can induce the differentiation of HSCs.

NRs and Embryonic Stem Cells

In addition to their role in regulating hematopoiesis, several NRs function in regulating the maintenance and differentiation of embryonic stem (ES) cells (86) The estrogen-related receptor β (Esrrβ) subfamily of NRs contains three isoforms (α, β, γ). Luo et al. (87) and Pettersson et al. (88) reported that mice lacking Esrrβ have impaired trophoblast stem cell differentiation and failure of placenta development. After short hairpin RNA-induced silencing of Esrrβ, ES cells differentiated in culture, suggesting that Esrrβ repressed ES cell differentiation (89). Transcriptional analysis demonstrated that knockdown of Esrrβ altered the expression of a distinct family of genes compared with those regulated by the pluripotency genes Oct4, Sox2, and Nanog (86,89). These results suggested that Esrrβ represses ES cell differentiation via a pathway that is independent of Oct4-, Sox2-, and Nanog-mediated control of ES cell pluripotency (86,89).

Steroidogenic factor (SF-1) is an orphan NR that is expressed in steroidogenic tissues including the adrenal cortex, Leydig cells, Sertoli cells, the pituitary gland, and in the inner cell mass of mouse blastocysts (86,90,91). The proximal promoter of Oct4 contains a consensus SF-1 response motif, and when SF-1 is overexpressed, a 3-fold increase in Oct4 promoter activity is observed (86,92,93). RA-induced differentiation of ES cells causes a loss of expression of both SF-1 and Oct4, suggesting a role for SF-1 in the maintenance of ES cell pluripotency (86,92,93). Similarly, the liver receptor homolog-1 (LRH-1), another orphan nuclear receptor, is expressed by ES cells and the inner cell mass of the blastocyst (86,94) and binds to response elements in the Oct4 promoter region (86,94). LRH-1 knockout mice die at d 6.5–d 9.5, and both LRH-1 and Oct4 are simultaneously down-regulated in response to the differentiative effects of RA (86,92).

The dosage-sensitive sex reversal, adrenal hypoplasia congenital, locus on the X-chromosome, gene 1 (DAX1) is an orphan nuclear receptor that is also critical in initiation of steroidogenesis in development (86,95). Disruption of DAX1 by RNA interference or conditional knockout in ES cells caused ES cell differentiation (96), and treatment of ES cells with RA caused a decrease in DAX1 expression in parallel with decline in Oct4 (96). Taken together, these data suggest a role for DAX1 in repressing the differentiation of ES cells and a functional relationship with RA signaling in regulating ES cell differentiation.

The orphan NR germ cell nuclear factor (GCNF) is essential for normal embryonic development and survival and proper formation of the anterior-posterior axis (86,97,98). RA induces GCNF expression in ES cells, and GCNF binds to a conserved region in the Oct4 promoter, thereby repressing Oct4 expression and promoting ES cell differentiation (99). Examination of GCNF−/− ES cells confirmed that GCNF is required for RA-mediated repression of Oct4, Nanog, and Sox2 during ES cell differentiation (99). Interestingly, GCNF appears to mediate repression of Oct4 expression via modulation of DNA methylation (100). Taken together, these data indicate that GCNF is essential for the repression of pluripotency genes and in the initiation of differentiation of ES cells (86,97,98,99,100). In addition to Esrrβ, SF-1, LRH-1, DAX-1, and GCNF, systematic gene expression profiling of NRs has demonstrated diametric expression of certain NRs between murine and human ES cells (101). This dataset provides an important resource for understanding and testing the precise roles of NRs in murine and human ES cells (101).

NRs and Induced Pluripotent Stem Cells (iPS)

A major advancement in cell biology was the demonstration that adult fibroblasts could be reprogrammed to pluripotency (iPS) via retroviral-mediated transduction of the transcription factors Oct4, Sox2, C-myc, and Klf4 (102,103). Recently, Feng et al. (104) reported that the orphan NR, Esrrβ, could function in replacement of Klf4 in this process such that retroviral infection of fibroblasts with Esrrβ, Oct4, and Sox2 became pluripotent with equal multilineage differentiation capacity to cells infected with Oct4, Sox2, C-myc, and Klf4. The authors also showed that Esrrβ induced the expression of several ES cell-specific genes (104). Taken together, these results demonstrate that an NR, Esrrβ, can be targeted to reprogram somatic cells (104).

Synopsis

Although NRs are not generally considered dominant regulators of hematopoiesis, this review illustrates that several NRs have precise and complementary roles in regulating virtually all cell types within the hematopoietic hierarchy (Fig. 3). For example, HSC self-renewal and differentiation (RARγ and RXR), myelopoiesis (RARα, PPARγ, ERβ, Nur-77/Nor-1), erythropoiesis (AR, GR, TRα, RXR), B lymphopoiesis (ERβ, AR), and T lymphopoiesis (VDR) are all regulated by the action of NRs (Fig. 3). Recent studies have also shown deterministic functions of NRs and orphan NRs in controlling ES cell pluripotency and differentiation and iPS. As our ability to measure HSC and ES function in vitro and in vivo continues to evolve, additional roles for NRs in regulating HSC regeneration and tissue stem cells in general will be identified. Because NRs are particularly amenable to manipulation with small molecule ligands, they represent attractive targets for the therapeutic expansion of HSCs, or iPS cells, and to augment hematopoiesis in vivo.

Figure 3.

Schematic overview of NR regulation in hematopoiesis. NRs that have activating function are shown in green and repressive actions are shown in red. LTHSC, long-term repopulating hematopoietic stem cell; STHSC, short-term repopulating hematopoietic stem cell; MPP, multipotent progenitor cell; CMP, common myeloid progenitor cell; MEP, megakaryocyte-erythroid progenitor cell; GMP, granulocyte-monocyte progenitor cell; CLP, common lymphoid progenitor cell; RBC, red blood cell.