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Journal ArticleDOI

Self-Renewing Osteoprogenitors in Bone Marrow Sinusoids Can Organize a Hematopoietic Microenvironment

TL;DR: It is shown that MCAM/CD146-expressing, subendothelial cells in human BM stroma are capable of transferring, upon transplantation, the HME to heterotopic sites, coincident with the establishment of identical subendOThelial cells within a miniature bone organ.
About: This article is published in Cell.The article was published on 2007-10-19 and is currently open access. It has received 2093 citations till now. The article focuses on the topics: Hematopoietic stem cell niche & Stromal cell.
Citations
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Journal ArticleDOI
TL;DR: Blood vessel walls harbor a reserve of progenitor cells that may be integral to the origin of the elusive MSCs and other related adult stem cells.

3,638 citations


Cites background or result from "Self-Renewing Osteoprogenitors in B..."

  • ...Confirming and extending pre- vious observations (Ozerdem et al., 2002; Middleton et al., 2005; Sacchetti et al., 2007), we have validated the CD146+ NG2+ PDGFRb+ ALP+ CD34 CD45 vWF CD144 phenotype as an indicator of pericyte/perivascular cell identity throughout hu- man fetal and adult organs....

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  • ...Interestingly, a population of CD146+ subendothelial cells in human bone mar- row contains osteogenic progenitors that are also at the origin of the stromal cells that support hematopoiesis (Sacchetti et al., 2007)....

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  • ...…associated with pericytes during vascular morphogenesis (Ozerdem et al., 2002) and CD146 (aka S-endo1, Mel-CAM, Muc18, or gicerin), an endothelial cell antigen also expressed at the surface of peri- cytes (Li et al., 2003; Middleton et al., 2005; Sacchetti et al., 2007) (Figures 1A–1C and 1G)....

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  • ...for Mesenchymal Stem Cells in Multiple Human Organs...

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Journal ArticleDOI
TL;DR: The targets and mechanisms of M SC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches are discussed.
Abstract: Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.

3,142 citations


Cites background from "Self-Renewing Osteoprogenitors in B..."

  • ...However, in the bone marrow, stromal cells are a rare and heterogeneous population of cells that contain a mixture of progenitors at different stages of commitment to the mesodermal lineage and only a very small number of multipotential self-renewing stem cells, which have recently been identified as sub-endothelial cells that express CD146 (also known as MCAM...

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Journal ArticleDOI
12 Aug 2010-Nature
TL;DR: It is demonstrated that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
Abstract: The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.

3,012 citations

Journal ArticleDOI
16 Jan 2014-Nature
TL;DR: The haematopoietic stem cell niche remains incompletely defined and beset by competing models, and outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.
Abstract: Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.

1,899 citations

Journal ArticleDOI
22 Feb 2008-Cell
TL;DR: Niches are local tissue microenvironments that maintain and regulate stem cells that are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood.

1,809 citations


Cites background from "Self-Renewing Osteoprogenitors in B..."

  • ...Angiopoietin-1 expression has been attributed to both osteoblasts at the endosteum (Arai et al., 2004) and to perivascular mesenchymal progenitors (Sacchetti et al., 2007)....

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  • ...Perivascular reticular cells and mesenchymal progenitors have also been proposed to elaborate factors that regulate HSC maintenance (Sacchetti et al., 2007; Sugiyama et al., 2006)....

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  • ..., 2004) and to perivascular mesenchymal progenitors (Sacchetti et al., 2007)....

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  • ...The chemokine CXCL12 (SDF-1) is required for the maintenance of bone marrow HSCs and is expressed by both perivascular and endosteal cells (Kollet et al., 2006; Sacchetti et al., 2007; Sugiyama et al., 2006)....

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References
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Journal ArticleDOI
TL;DR: There is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities, and the exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values.
Abstract: SUMMARY In this paper we report exploratory analyses of high-density oligonucleotide array data from the Affymetrix GeneChip R � system with the objective of improving upon currently used measures of gene expression. Our analyses make use of three data sets: a small experimental study consisting of five MGU74A mouse GeneChip R � arrays, part of the data from an extensive spike-in study conducted by Gene Logic and Wyeth’s Genetics Institute involving 95 HG-U95A human GeneChip R � arrays; and part of a dilution study conducted by Gene Logic involving 75 HG-U95A GeneChip R � arrays. We display some familiar features of the perfect match and mismatch probe ( PM and MM )v alues of these data, and examine the variance–mean relationship with probe-level data from probes believed to be defective, and so delivering noise only. We explain why we need to normalize the arrays to one another using probe level intensities. We then examine the behavior of the PM and MM using spike-in data and assess three commonly used summary measures: Affymetrix’s (i) average difference (AvDiff) and (ii) MAS 5.0 signal, and (iii) the Li and Wong multiplicative model-based expression index (MBEI). The exploratory data analyses of the probe level data motivate a new summary measure that is a robust multiarray average (RMA) of background-adjusted, normalized, and log-transformed PM values. We evaluate the four expression summary measures using the dilution study data, assessing their behavior in terms of bias, variance and (for MBEI and RMA) model fit. Finally, we evaluate the algorithms in terms of their ability to detect known levels of differential expression using the spike-in data. We conclude that there is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities. ∗ To whom correspondence should be addressed

10,711 citations

Journal ArticleDOI
TL;DR: The study of mesenchymal stem cells, whether isolated from embryos or adults, provides the basis for the emergence of a new therapeutic technology of self‐cell repair.

4,861 citations

Journal ArticleDOI
TL;DR: The bone marrow contains multipotent MSC, which can be easily isolated and cultured in vitro, and the possibility of their clinical use in cell and gene therapy is analyzed.
Abstract: Institute of Biological Medicine, Moscow The formation of the concept of a mesenchymal stem cell (MSC) is a priority of Russian biological science. A. Ya. Fridenshtein and his colleagues were the first who experimentally proved the existence of MSC. Osteogenic potential of fibroblastlike bone marrow cells of different mammalian species was demonstrated [25,26]. Fibroblast-like bone marrow cells often formed discrete adhesive colonies in vitro [27,28,47]. After heteroand orthotopic transplantation in vivo cloned cells from these colonies formed bone, cartilaginous, fibrous, and adipose tissues [48]. Intensive self-renewal and multipotency of fibroblast-like colony-forming cells from the bone marrow allowed Fridenshtein and Owen to formulate a concept of multipotent mesenchymal precursor cells (MPC) [62]. An ordered chain of finely regulated cell proliferation, migration, differentiation, and maturation processes underlies the formation of the majority of cell lineages in adult organisms. The earliest cell elements in this chain are stem cells (SC). Along with extensive self-renewal capacity, SC possess a great differentiation potential. Apart from well studied hemopoietic and intestinal SC, other SC classes were recently discovered in adult organism. Until recently it was considered that SC in adults can give rise to cell lines specific to tissues where these cells are located; however, new facts necessitated revision of this concept. Hemopoietic SC capable of differentiating into all cell elements of the blood, can also be a source of hepatic oval cells [65]; neural SC, precursors of neurons and glia [2,3], serve as the source of early and committed hemopoietic precursors [10]. MSC, a source of bone, cartilaginous, and adipose tissue cells, can differentiate into neural cells [46]. Tissue growth and reparation are associated with migration of uncommitted precursor cells from other tissues. During muscle tissue reparation mesenchymal SC migrate from the bone marrow into skeletal muscles [24]. Hence, in addition to capacity to unlimited division and reproduction of a wide spectrum of descendants of a certain differentiation line, adult SC are characterized by high plasticity. The existence of a rare type of somatic pluripotent SC, common precursors of all SC in an adult organism, is hypothesized [79]. Another important characteristic of SC is their migration from the tissue niche into circulation, which was experimentally proven for hemopoietic and MSC [69,73]. For activation of the differentiation program, circulating SC should get into an appropriate microenvironment [75,78]. A potent stimulus for investigation of SC is the possibility of their clinical use in cell and gene therapy. The bone marrow contains multipotent MSC, which can be easily isolated and cultured in vitro. It is therefore interesting to analyze some fundamental aspects of MSC biology and the possibilities of their clinical use. MSC descendants are involved in the formation of bones, cartilages, tendons, adipose and muscle tissues, and stroma maintaining the hemopoiesis [12,19,51]. The term MPC is used to denote MSC and their committed descendants capable of differentiating into at least two types of mature cells, which are present in the bone marrow and some mesenchymal tissues [16,19,57,82].

3,582 citations


"Self-Renewing Osteoprogenitors in B..." refers background in this paper

  • ...The multipotency of at least a subset of CFU-Fs supports the view that a second type of stem cell (skeletal [Bianco and Robey, 2004], stromal [Owen and Friedenstein, 1988], or ‘‘mesenchymal’’ [Caplan, 1991]) coexists with HSCs in BM....

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  • ...…CFU-Fs supports the view that a second type of stem cell (skeletal [Bianco and Robey, 2004], stromal [Owen and Friedenstein, 1988], or ‘‘mesenchymal’’ [Caplan, 1991]) coexists with HSCs in BM. Due to the lack of markers suited to bridge the gap between in situ, ex vivo, and in vivo observations,…...

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Journal ArticleDOI
23 Oct 2003-Nature
TL;DR: Osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation.
Abstract: Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.

3,434 citations


"Self-Renewing Osteoprogenitors in B..." refers background in this paper

  • ...The multipotency of at least a subset of CFU-Fs supports the view that a second type of stem cell (skeletal [Bianco and Robey, 2004], stromal [Owen and Friedenstein, 1988], or ‘‘mesenchymal’’ [Caplan, 1991]) coexists with HSCs in BM. Due to the lack of markers suited to bridge the gap between in situ, ex vivo, and in vivo observations, the in situ counterpart of CFU-Fs has previously remained unknown, and the Cell 131, 324–336, October 19, 2007 ª2007 Elsevier Inc. 331 (A) Ang-1 immunoreactivity in sections of human BM is restricted to ARCs (arrows) and absent over bone surfaces. ad, adipocytes....

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  • ...For example, CD146+ subendothelial cells ex- 334 Cell 131, 324–336, October 19, 2007 ª2007 Elsevier Inc. pressing HSC regulators such as Ang-1 or CXCL12 would be strategically positioned to facilitate the homing of blood borne hematopoietic progenitors to the marrow environment or to contribute to a steady-state sinusoidal niche where HSCs can be localized....

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  • ...As (self-renewing) progenitors of sinusoidal adventitial reticular cells, CD146+ stromal cells contribute to the organization, and become an integral part, of the structure of sinusoidal walls, in the vicinities of which HSCs have been directly localized (Kiel et al., 2005)....

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  • ...A body of evidence also suggests that endosteal (Calvi et al., 2003; Zhang et al., 2003) and sinusoidal surfaces (Kiel et al., 2005), but also CXCL12-expressing ‘‘reticular’’ cells within the hematopoietic space (Sugiyama et al., 2006), may represent specific sites of HSC regulation (‘‘niches’’)....

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  • ...Cell 131, 324–336, October 19, 2007 ª2007 Elsevier Inc. 333 ligand of the Tie-2 receptor that is specifically expressed in ECs and HSCs, Ang-1 plays pivotal roles both in angiogenesis and hematopoiesis....

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Journal ArticleDOI
01 Jul 2005-Cell
TL;DR: This work compared the gene expression profiles of highly purified HSCs and non-self-renewing multipotent hematopoietic progenitors and found that both groups occupied multiple niches, including sinusoidal endothelium in diverse tissues.

3,091 citations


"Self-Renewing Osteoprogenitors in B..." refers background in this paper

  • ..., 2003), as well as to endothelial cells lining sinusoids (Kiel et al., 2005), suggesting a potential multiplicity of physiologically important...

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  • ...and sinusoidal surfaces (Kiel et al., 2005), but also CXCL12-expressing ‘‘reticular’’ cells within the hematopoietic space (Sugiyama et al....

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  • ...As (self-renewing) progenitors of sinusoidal adventitial reticular cells, CD146+ stromal cells contribute to the organization, and become an integral part, of the structure of sinusoidal walls, in the vicinities of which HSCs have been directly localized (Kiel et al., 2005)....

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  • ...A body of evidence also suggests that endosteal (Calvi et al., 2003; Zhang et al., 2003) and sinusoidal surfaces (Kiel et al., 2005), but also CXCL12-expressing ‘‘reticular’’ cells within the hematopoietic space (Sugiyama et al., 2006), may represent specific sites of HSC regulation (‘‘niches’’)....

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  • ...of sinusoidal walls, in the vicinities of which HSCs have been directly localized (Kiel et al., 2005)....

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