The stem cell niche

Walker, Monica R.; Patel, Khushbu; Stappenbeck, Thaddeus S.

doi:10.1002/path.2474

Cited by 190 publications

(128 citation statements)

References 122 publications

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“…As hypothesized by Walker and colleagues, the adult stem cell microenvironment is maintained by physical contact and a defined set of diffusible factors. (27) When this microenvironment changes, as is the case with damaged muscle, mrSCs can proliferate, differentiate, and actively participate in the regeneration process. As such, mrSCs have to be considered as potent cells involved in HO pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

Leblanc

Trensz

Haroun

et al. 2010

Journal of Bone and Mineral Research

112

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Heterotopic ossification (HO) is defined as the formation of bone inside soft tissue. Symptoms include joint stiffness, swelling, and pain. Apart from the inherited form, the common traumatic form generally occurs at sites of injury in damaged muscles and is often associated with brain injury. We investigated bone morphogenetic protein 9 (BMP-9), which possesses a strong osteoinductive capacity, for its involvement in muscle HO physiopathology. We found that BMP-9 had an osteoinductive influence on mouse muscle resident stromal cells by increasing their alkaline phosphatase activity and bone-specific marker expression. Interestingly, BMP-9 induced HO only in damaged muscle, whereas BMP-2 promoted HO in skeletal muscle regardless of its state. The addition of the soluble form of the ALK1 protein (the BMP-9 receptor) significantly inhibited the osteoinductive potential of BMP-9 in cells and HO in damaged muscles. BMP-9 thus should be considered a candidate for involvement in HO physiopathology, with its activity depending on the skeletal muscle microenvironment. ß

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Section: Introductionmentioning

confidence: 99%

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

Leblanc

Trensz

Haroun

et al. 2010

Journal of Bone and Mineral Research

112

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“…More recently, it has been demonstrated by in vivo studies that hMSCs can transdifferentiate into endoderm-derived cells and cardiomyocytes (Toma et al , 2002 ;Sato et al , 2005 ). The central characteristics of stem cells are their capa city for self-renewal and differentiation (Weissman , 2000 ), which is tightly regulated within the stem cell niche (Spradling et al , 2001 ;Walker et al , 2009 ). The control of stem cell niches is emerging as a key role of MSCs in a broad range of tissues.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells

Kolben¹,

Peröbner²,

Fernsebner³

et al. 2012

Biological Chemistry

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Wnt/ β -catenin signaling is of fundamental importance in the regulation of self-renewal, migration/ invasion, and differentiation of human mesenchymal stem cells (hMSCs). Because little information is available about the function of Frizzled receptors (Fzds) as the main receptors of Wnt proteins in hMSCs, we first performed comparative Fzd mRNA expression profiling. Fzd9 and Fzd10 were not expressed in hMSCs. While Fzd3 was expressed at low levels in hMSCs, the other Fzds exhibited high expression rates. Activation and repression of Wnt signaling in hMSCs revealed that the expression levels of Fzd1, Fzd6, and Fzd7 are positively correlated with the Wnt/ β -catenin activation status, whereas Fzd8 exhibited an inverse relation. For studying the functional relevance of Fzds in Wnt/ β -catenin signaling, RNA interference, ectopic expression studies, and rescue approaches were performed in hMSCs carrying a highly sensitive TCF/LEF reporter gene system ( Gaussia luciferase). We found that, Fzd1, Fzd5, Fzd7, and Fzd8 are largely involved in Wnt/ β -catenin signaling of hMSCs. Moreover, the knockdown of Fzd5 can be compensated by the ectopic expression of Fzd7. Conversely, the ectopic expression of Fzd5 in Fzd7-knockdown hMSCs resulted in a rescue of Wnt/ β -catenin signaling, pointing to a functional redundancy of Fzd5 and Fzd7.

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“…Apart from the existence of genetically distinctive non-modal populations, intra-tumour phenotypic diversity can be explained by non-genetic mechanisms, including epigenetic regulation of genes Intra-tumour genetic heterogeneity in breast cancer 563 and molecular networks, epithelial-to-mesenchymal transition, interaction with specific niches and tumour microenvironment [2,[7][8][9][10][11], and by the 'cancer stem cell' hypothesis [12][13][14][15][16]. This hypothesis proposes that the intra-tumour heterogeneity stems from, and is maintained by, a small population of cells (the socalled 'cancer stem cells'), which give rise to more differentiated cells and thus create the phenotypic diversity of tumours [2,12,15,16].…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

Geyer

Weigelt

Natrajan

et al. 2010

The Journal of Pathology

187

159

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Cancers may be composed of multiple populations of submodal clones sharing the same initiating genetic lesions, followed by the acquisition of divergent genetic hits. Intra-tumour genetic heterogeneity has profound implications for cancer clinical management. To determine the extent of intra-tumour genetic heterogeneity in breast cancers, and whether the morphological diversity of breast cancers is underpinned by divergent genetic aberrations, we analysed the genomic profiles of microdissected, morphologically distinct components of six metaplastic breast carcinomas, tumours characterized by the presence of morphological areas with divergent differentiation. Each morphologically distinct component was separately microdissected and subjected to high-resolution microarray-based comparative genomic hybridization. Each component was also analysed by immunohistochemistry and in situ hybridization. Clonal relationship between the distinct components was tested by TP53 sequencing and human androgen receptor (HUMARA) X-chromosome inactivation assay. In the majority of cases, all morphologically distinct components from each case were clonal and displayed remarkably similar genetic profiles. In two cases, however, morphologically distinct components harboured specific genetic aberrations. In an adenosquamous carcinoma, the differences were such that only 20% of the genome harboured similar copy number changes. The squamous component displayed EGFR gene amplification, EGFR over-expression and lack of expression of hormone receptors, whereas the lobular component displayed the reverse pattern. The components of a biphasic spindle cell carcinoma harboured similar gains, losses, amplifications of 9p23 and 17q12 (HER2 ) and identical TP53 mutations, suggesting that these were relatively early events in the development of this tumour; however, each component displayed divergent focal amplifications. Importantly, the metastatic deposit of this case, despite harbouring a TP53 mutation identical to that found in the primary tumour, harboured additional specific focal amplifications. This proof-of-principle study provides direct evidence of intra-tumour genetic heterogeneity in breast cancers, and shows that in some cases morphological diversity may be underpinned by distinct genetic aberrations.

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The stem cell niche

Cited by 190 publications

References 122 publications

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

BMP-9-induced muscle heterotopic ossification requires changes to the skeletal muscle microenvironment

Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells

Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas

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