What is the true nature of the osteoblastic hematopoietic stem cell niche?

Askmyr, Maria; Sims, Natalie A.; Martın, Thomas; Purton, Louise E.

doi:10.1016/j.tem.2009.03.004

Cited by 88 publications

(76 citation statements)

References 65 publications

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“…A microarray analysis of mRNA comparing the Med1 ϩ/ϩ and Med1 Ϫ/Ϫ MEFs disclosed approximately 15 genes whose expression levels were profoundly attenuated (data deposited in GEO, accession number GSE22471). Among the molecules encoded by these genes, only OPN was a known molecule that has activity in niche (2,16). The level of Opn mRNA was high in Med1 ϩ/ϩ MEFs, similar to that in the MC3T3-E1 and OP-9 cells; it was significantly downregulated in the Med1 Ϫ/Ϫ MEFs and restored to the control level in the Rev-Med1 Ϫ/Ϫ MEFs ( Fig.…”

Section: Mefs As An In Vitro Niche Model Since the Use Of Med1mentioning

confidence: 70%

The Transcriptional Mediator Subunit MED1/TRAP220 in Stromal Cells Is Involved in Hematopoietic Stem/Progenitor Cell Support through Osteopontin Expression

Sumitomo

Ishino

Urahama

et al. 2010

Molecular and Cellular Biology

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MED1/TRAP220, a subunit of the transcriptional Mediator/TRAP complex, is crucial for various biological events through its interaction with distinct activators, such as nuclear receptors and GATA family activators. In hematopoiesis, MED1 plays a pivotal role in optimal nuclear receptor-mediated myelomonopoiesis and GATA-1-induced erythropoiesis. In this study, we present evidence that MED1 in stromal cells is involved in supporting hematopoietic stem and/or progenitor cells (HSPCs) through osteopontin (OPN) expression. We found that the proliferation of bone marrow ( The specialized microenvironmental niches in the bone marrow (BM), namely, the osteoblastic (or endosteal) and vascular niches, host and interface with hematopoietic stem cells (HSCs) and are the sites where their size and fate are strictly regulated (15, 29; reviewed in references 1, 16, 28, 30, and 34). HSCs and their niches produce diverse molecules, whose interactions control HSC self-renewal and differentiation. In the osteoblastic niche, almost 75% of the HSCs are in a quiescent (slowly cycling or G 0 ) state. In a physiological condition, HSCs migrate from the osteoblastic niche toward the vascular niche, enter the cell cycle, and undergo symmetric cell division or asymmetric division, accompanied by differentiation and final maturation. In this manner, a defined set of mature differentiated progeny is continuously produced without HSC depletion.The transcriptional Mediator complex, originally isolated as a thyroid hormone receptor-associated protein (TRAP) complex and subsequently identified as a mammalian counterpart of the yeast Mediator complex (i.e., a subcomplex of the RNA polymerase II holoenzyme), appears to serve as a bridge between diverse activators and the general transcriptional machinery (reviewed in references 4, 13, 18, and 21). This complex contains approximately 25 polypeptides, among which the MED1/TRAP220 subunit is responsible for specific binding of the complex to several activators, which include nuclear receptors (13), GATA family members (22, 27), C/EBP␤ (20), and BRCA1 (33). Mediator conveys the specific signals of the activators to the recruited general transcriptional machinery to activate transcription by direct communication between MED1 and the activators (5).Through the interaction with MED1, nuclear receptors are involved in various hematocytic differentiations. For example, the vitamin D receptor (VDR) and retinoic acid receptor (RAR) are members of the nuclear hormone receptor superfamily, whose interaction with MED1 is crucial for liganddependent monopoiesis and granulopoiesis, respectively, as well as for peroxisome proliferator-activated receptor ␥ (PPAR␥)-mediated adipogenesis (7, 31). GATA-1, for which MED1 was recently shown to be a specific coactivator, mediates erythropoiesis through its interaction with MED1 (27). However, as Med1 null mice die early during embryogenesis (12,22), it is difficult to determine the physiological role of MED1 in BM hematopoiesis in vivo.Osteopontin (OPN), an acidic glyc...

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Section: Mefs As An In Vitro Niche Model Since the Use Of Med1mentioning

confidence: 70%

The Transcriptional Mediator Subunit MED1/TRAP220 in Stromal Cells Is Involved in Hematopoietic Stem/Progenitor Cell Support through Osteopontin Expression

Sumitomo

Ishino

Urahama

et al. 2010

Molecular and Cellular Biology

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“…In mouse, the adventitial reticular cell population is thought to be identical with the CAR cell population that has been shown to be involved in hematopoietic stem cell biology. 45,46 Figure 5 Model of the CD271 þ mesenchymal stromal cell (MSC) niche for CD34 þ hematopoietic progenitor/stem cells (HSPCs) in human bone marrow and its perturbation in myelodysplastic syndrome (MDS). (a) In benign bone marrow, the majority of the CD34 þ HSPCs are located in intimate cellcell contact with CD271 þ MSCs.…”

Section: Discussionmentioning

confidence: 99%

Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

Flores-Figueroa

Varma

Montgomery

et al. 2012

Laboratory Investigation

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“…Homeostasis of this microenvironment is essential as an imbalance favoring one cell type can affect the regulation and function of the other (77). Therefore Zfp467 may play a fundamental role in bone and blood-related disorders.…”

Section: Discussionmentioning

confidence: 99%

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

Quach

Walker

Allan

et al. 2011

Journal of Biological Chemistry

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Osteoblasts and adipocytes are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. cDNA microarrays and quantitative real-time PCR (Q-PCR) were carried out in a differentiating mouse stromal osteoblastic cell line, Kusa 4b10, to identify gene targets of factors that stimulate osteoblast differentiation including parathyroid hormone (PTH) and gp130-binding cytokines, oncostatin M (OSM) and cardiotrophin-1 (CT-1). Zinc finger protein 467 (Zfp467) was rapidly downregulated by PTH, OSM, and CT-1. Retroviral overexpression and RNA interference for Zfp467 in mouse stromal cells showed that this factor stimulated adipocyte formation and inhibited osteoblast commitment compared with controls. Regulation of adipocyte markers, including peroxisome proliferator-activated receptor (PPAR) ␥, C/EBP␣, adiponectin, and resistin, and late osteoblast/osteocyte markers (osteocalcin and sclerostin) by Zfp467 was confirmed by Q-PCR. Intra-tibial injection of calvarial cells transduced with retroviral Zfp467 doubled the number of marrow adipocytes in C57Bl/6 mice compared with vector control-transduced cells, providing in vivo confirmation of a pro-adipogenic role of Zfp467. Furthermore, Zfp467 transactivated a PPAR-response element reporter construct and recruited a histone deacetylase complex. Thus Zfp467 is a novel co-factor that promotes adipocyte differentiation and suppresses osteoblast differentiation. This has relevance to therapeutic interventions in osteoporosis, including PTH-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering.Osteoblasts and adipocytes are derived from a common subpopulation of mesenchymal stem cell (MSC) 4 progenitors.MSC lineage commitment is dependent on the expression of key transcription factors that, on induction, initiate a cascade of events culminating in cellular differentiation and development. Among the transcription factors regulated, osteoblast differentiation requires expression of Runx2 (1, 2) to commit progenitors to preosteoblasts, with Osterix (3), ATF4 (4), and AP-1 (5) promoting their transition to functional osteoblasts. Alternately, adipocytic differentiation requires expression of different key regulators, peroxisome proliferator-activated receptor ␥ (PPAR␥) (6) and members of the CCAAT/enhancer-binding protein family (C/EBPs) (7). Because osteoblasts and adipocytes are derived from common progenitors, lineage determination of precursor cells to osteoblasts results in a proportional decrease in adipogenesis. This inverse relationship is observed clinically; an increase in marrow adiposity is associated with age-related osteoporosis (8) and conditions that induce bone loss, such as ovariectomy (9) and immobilization (10). Conversely, high bone mass due to increased osteoblast commitment is associated with reduced adipocyte differentiation (5). The molecular mechanisms by which lineage...

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What is the true nature of the osteoblastic hematopoietic stem cell niche?

Cited by 88 publications

References 65 publications

The Transcriptional Mediator Subunit MED1/TRAP220 in Stromal Cells Is Involved in Hematopoietic Stem/Progenitor Cell Support through Osteopontin Expression

The Transcriptional Mediator Subunit MED1/TRAP220 in Stromal Cells Is Involved in Hematopoietic Stem/Progenitor Cell Support through Osteopontin Expression

Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow

Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment

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