Disruption of Heparan and Chondroitin Sulfate Signaling Enhances Mesenchymal Stem Cell-Derived Osteogenic Differentiation via Bone Morphogenetic Protein Signaling Pathways

Manton, Kerry J.; Leong, Denise Fong Mei; Cool, Simon M.; Nurcombe, Victor

doi:10.1634/stemcells.2007-0065

Cited by 94 publications

(66 citation statements)

References 58 publications

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“…This observation is in agreement with previous reports showing that HS depletion by heparinase treatment or by knockdown of the PAPST, the transporter that transports PAPS from cytosol to Golgi for sulfation modification at HS biosynthesis, both attenuated BMP signaling in mESCs (29,44). Interestingly, Manton et al observed that HS depletion by heparinase treatment enhanced BMP signaling in human mesenchymal stem cells during differentiation into osteoblasts (48), indicating that HS functions to inhibit BMP signaling in the context of human mesenchymal stem cells. The positive and negative regulatory roles of HS in BMP signaling have been also observed during embryogenesis in EXT1-or NDST1-deficient mice, respectively (37,49).…”

Section: Discussionsupporting

confidence: 92%

Heparan Sulfate Facilitates FGF and BMP Signaling to Drive Mesoderm Differentiation of Mouse Embryonic Stem Cells

Kraushaar

Rai

Condac

et al. 2012

Journal of Biological Chemistry

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Background: HS has been implicated in regulating ESC differentiation. Results: Mouse ESCs lacking EXT1 fail to differentiate into mesoderm. Restoration of the FGF and BMP signaling each partially rescued the mesoderm differentiation defect. Conclusion: HS facilitates FGF and BMP signaling to drive mesoderm differentiation. Significance: This study shows that HS essentially promotes mesoderm differentiation of mouse ESCs.

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Section: Discussionsupporting

confidence: 92%

Heparan Sulfate Facilitates FGF and BMP Signaling to Drive Mesoderm Differentiation of Mouse Embryonic Stem Cells

Kraushaar

Rai

Condac

et al. 2012

Journal of Biological Chemistry

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“…BMPs mediate their signals through phosphorylation of specific receptor-associated Smads, which then complex with other Smads, translocate to the nucleus, and affect gene transcription. We explored whether, under basal conditions, sFRP2 overexpression altered the transcript levels of BMP2, known to play a role in both osteogenic and chondrogenic commitment (12,13). Baseline relative transcript levels of BMP2 were similar in both groups (Fig.…”

Section: Sfrp2 Increases Msc Engraftment and Inhibits Canonical Wntmentioning

confidence: 99%

“…Canonical Wnt signaling directs osteogenic differentiation of MSCs by stimulating the expression of osteocalcin (10), this pathway is also involved in early chondrogenesis (11). The BMP pathway also modulates osteogenic differentiation of MSCs by controlling osteocalcin (12), and BMP2 induces chondrocyte fate determination (13). The Wnt cascade is involved in other cellular processes besides differentiation; canonical Wnt signaling inhibition, through the activity of Dkk-1, increases human MSC proliferation without overt differentiation (14).…”

mentioning

confidence: 99%

sFRP2 Suppression of Bone Morphogenic Protein (BMP) and Wnt Signaling Mediates Mesenchymal Stem Cell (MSC) Self-renewal Promoting Engraftment and Myocardial Repair

Alfaro

Vincent

Saraswati

et al. 2010

Journal of Biological Chemistry

107

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Transplantation of mesenchymal stem cells (MSCs) is a promising therapy for ischemic injury; however, inadequate survival of implanted cells in host tissue is a substantial impediment in the progress of cellular therapy. Secreted Frizzled-related protein 2 (sFRP2) has recently been highlighted as a key mediator of MSC-driven myocardial and wound repair. Notably, sFRP2 mediates significant enhancement of MSC engraftment in vivo. We hypothesized that sFRP2 improves MSC engraftment by modulating self-renewal through increasing stem cell survival and by inhibiting differentiation. In previous studies we demonstrated that sFRP2-expressing MSCs exhibited an increased proliferation rate. In the current study, we show that sFRP2 also decreased MSC apoptosis and inhibited both osteogenic and chondrogenic lineage commitment. sFRP2 activity occurred through the inhibition of both Wnt and bone morphogenic protein (BMP) signaling pathways. sFRP2-mediated inhibition of BMP signaling, as assessed by levels of pSMAD 1/5/8, was independent of its effects on the Wnt pathway. We further hypothesized that sFRP2 inhibition of MSC lineage commitment may reduce heterotopic osteogenic differentiation within the injured myocardium, a reported adverse side effect. Indeed, we found that sFRP2-MSC-treated hearts and wound tissue had less ectopic calcification. This work provides important new insight into the mechanisms by which sFRP2 increases MSC self-renewal leading to superior tissue engraftment and enhanced wound healing.Bone marrow-derived mesenchymal stem cells (MSCs) 2 are an attractive candidate for cell-mediated wound repair. Because of their plasticity, MSCs have been utilized in several preclinical and clinical trials of tissue regeneration (1).3 MSCs have been able to repair infarcted myocardium, bone, and soft tissue, albeit with varying degrees of success (3). These promising results are inconsistent, partly due to the low levels of engraftment of MSCs within the injured tissues (4). Hence, strategies to increase survival and engraftment within the wound may enhance MSC therapy.Self-renewal is an intrinsic property of stem cells that allows them to give rise to non-differentiated daughter cells by proliferating, preventing apoptosis, and avoid lineage commitment (5, 6). This process is important for the maintenance of a stem cell pool that, in the case of MSCs, can exert a more robust effect within the context of a wound. Although several cytokines, growth factors, adhesion molecules, and extracellular matrix components have been identified as cues that signal MSCs to differentiate, the molecular signals that modulate MSC self-renewal remain unknown (5). Data from the hematopoietic stem cell (HSC) field have documented the involvement of Wnt, Notch, and BMP signaling cascades in self-renewal; these pathways are implicated in the expansion of undifferentiated HSCs that upon transplantation into lethally irradiated mice successfully reconstitute the cleared bone marrow (7-9). Although no data are available to demonstrate the...

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“…To confirm this, we treated MX2 matrices with heparinase I, II, III and chondroitinase ABC. Heparinase and chondroitinase are heparin sulfate and chondroitin sulphate degrading enzymes that cleave GAG chains [75].…”

Section: Discussionmentioning

confidence: 99%

Comparative Gene Expression Profiling of Stromal Cell Matrices that Support Expansion of Hematopoietic Stem/Progenitor Cells

Lefevre¹

2013

J Stem Cell Res Ther

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The bone marrow microenvironment maintains a stable balance between self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs). This microenvironment, also termed the "hematopoietic niche", is primarily composed of stromal cells and their extracellular matrices (ECM) that jointly regulate HSPC functions. Previously, we have demonstrated that umbilical cord blood derived HSPCs can be maintained and expanded on stromal cell derived acellular matrices that mimic the complexity of the hematopoietic niche. The results indicated that matrices prepared at 20% O 2 with osteogenic medium (OGM) were best suited for expanding committed HSPCs, whereas, matrices prepared at 5% O 2 without OGM were better for primitive progenitors. Based upon these results we proposed that individual constituents of these matrices could be responsible for regulation of specific HSPC functions. To explore this hypothesis, we have performed comparative transcriptome profiling of these matrix producing cells, which identified differential expression of both known niche regulators, such as Wnt4, Angpt2, Vcam and Cxcl12, as well as genes not previously associated with HSPC regulation, such as Depp. MetaCore analysis of the differentially expressed genes suggests the down-regulation of several ECM related pathways and up-regulation of Ang-Tie2 and Wnt signaling pathways in OGM under high O 2 (20%). Our findings provide an overview of several known and unique genes and pathways that play potential key roles in the support of HSPCs by stromal cells, both ex vivo and in vivo, and could be helpful in understanding the complex network of signaling and communication in hematopoietic niches.

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Disruption of Heparan and Chondroitin Sulfate Signaling Enhances Mesenchymal Stem Cell-Derived Osteogenic Differentiation via Bone Morphogenetic Protein Signaling Pathways

Cited by 94 publications

References 58 publications

Heparan Sulfate Facilitates FGF and BMP Signaling to Drive Mesoderm Differentiation of Mouse Embryonic Stem Cells

Heparan Sulfate Facilitates FGF and BMP Signaling to Drive Mesoderm Differentiation of Mouse Embryonic Stem Cells

sFRP2 Suppression of Bone Morphogenic Protein (BMP) and Wnt Signaling Mediates Mesenchymal Stem Cell (MSC) Self-renewal Promoting Engraftment and Myocardial Repair

Comparative Gene Expression Profiling of Stromal Cell Matrices that Support Expansion of Hematopoietic Stem/Progenitor Cells

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