The role of bFGF on the ability of MSC to activate endogenous regenerative mechanisms in an ectopic bone formation model

Tasso, Roberta; Gaetani, Massimiliano; Molino, Erica; Cattaneo, Angela; Monticone, Massimiliano; Bachi, Ángela; Cancedda, Ranieri

doi:10.1016/j.biomaterials.2011.11.043

Cited by 75 publications

(58 citation statements)

References 38 publications

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“…The origin of the blood vessels was murine and no human cells differentiated into endothelial cells, indicating an indirect angiogenic effect rather than a direct differentiation of the cells. This was also confirmed by the fact that the UC-MSC secretome (CM) alone was capable of significantly inducing angiogenesis [49,51]. This effect was mediated only by UCMSCs, excluding the possible role of endothelial progenitor contaminants as previously demonstrated [6].…”

Section: Discussionsupporting

confidence: 57%

Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration

Todeschi

Backly

Capelli

et al. 2015

Stem Cells and Development

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Umbilical cord mesenchymal stem cells (UC-MSCs) show properties similar to bone marrow mesenchymal stem cells (BM-MSCs), although controversial data exist regarding their osteogenic potential. We prepared clinical-grade UC-MSCs from Wharton's Jelly and we investigated if UC-MSCs could be used as substitutes for BM-MSCs in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UCMSCs were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-sized calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSCs were first transduced with the luciferase gene. Angiogenic properties of UC-MSCs were tested using the mouse metatarsal angiogenesis assay. Cell secretomes were screened for the presence of various cytokines using an array assay. Analysis of implanted scaffolds showed that UC-MSCs, contrary to BM-MSCs, remained detectable in the implants for 3 weeks at most and did not induce bone formation in an ectopic location. Instead, they induced a significant increase of blood vessel ingrowth. In agreement with these observations, UC-MSC-conditioned medium presented a distinct and stronger proinflammatory/chemotactic cytokine profile than BM-MSCs and a significantly enhanced angiogenic activity. When UC-MSCs were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSCs. However, at variance with BM-MSCs, the new bone was deposited through the activity of stimulated host cells, highlighting the importance of the microenvironment on determining cell commitment and response. Therefore, we propose, as therapy for bone lesions, the use of allogeneic UC-MSCs by not depositing bone matrix directly, but acting through the activation of endogenous repair mechanisms.

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Section: Discussionsupporting

confidence: 57%

Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration

Todeschi

Backly

Capelli

et al. 2015

Stem Cells and Development

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“…We previously reported that the murine MSCs capacity to activate endogenous regenerative mechanisms was critically dependent on their commitment level. We observed that MSCs expanded in vitro in the presence of FGF-2, but not MSCs expanded in the absence of the factor, were capable of inducing host regenerative responses in vivo leading to a bone formation by the recipient cells [10]. It therefore, appears that either the existence of species-specific intercellular signals, or the conditions of expansion in vitro, or both, could be critical in determining the nature and the origin of the cells playing a role in the new bone deposition.…”

mentioning

confidence: 83%

“…Moreover, we demonstrated that MSCs, in an inflammatory environment, secreted a large amount of PGE 2 playing a key role in the macrophage polarization. Among the several biological functions hypothesized as related to the trophic effects of MSCs [26], the most significantly upregulated by FGF-2 were immune response, inflammatory response, response to wounding, and chemotaxis; thus, suggesting that a ''wound'' signature was induced in MSCs in presence of this factor [10]. Indeed, the bulk of cytokines and chemokines upregulated in treated cells contributed to orchestrate a microenvironment typically activated during wound healing and repair.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported the enhancement of some biological processes, including inflammation and innate immunity in MSCs grown in FGF-2 [10]. In particular, chemokines implicated in monocyte recruitment from the blood to inflamed tissues, such as CCL8 (monocyte chemoattractant protein 2) and CCL9 (macrophage inflammatory protein-1 gamma), were oversecreted.…”

Section: Different Macrophage Populations Infiltrate the Implanted Scmentioning

confidence: 99%

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In Vivo Implanted Bone Marrow-Derived Mesenchymal Stem Cells Trigger a Cascade of Cellular Events Leading to the Formation of an Ectopic Bone Regenerative Niche

Tasso

UliviValentina

ReverberiDaniele

et al. 2013

Stem Cells and Development

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We recently reported that mouse bone marrow stromal cells, also known as bone marrow (BM)-derived mesenchymal stem cells (MSCs), seeded onto a scaffold and implanted in vivo, led to an ectopic bone deposition by host cells. This MSCs capacity was critically dependent on their commitment level, being present only in MSCs cultured in presence of fibroblast growth factor-2. Taking advantage of a chimeric mouse model, in this study we show that seeded MSCs trigger a cascade of events resulting in the mobilization of macrophages, the induction of their functional switch from a proinflammatory to a proresolving phenotype, and the subsequent formation of a bone regenerative niche through the recruitment, within the first 2 weeks of implantation, of endothelial progenitors and of cells with an osteogenic potential (CD146 + CD105 + ), both of them derived from the BM. Moreover, we demonstrated that, in an inflammatory environment, MSCs secrete a large amount of prostaglandin E 2 playing a key role in the macrophage phenotype switch.

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“…16 FGF2 also selects MSCs best suited for ectopic bone formation. 17 Healthy bone is a balance between bone formation by osteoblasts and bone resorption by osteoclasts. The alteration of this balance is a feature of some autoimmune diseases (AD) such as rheumatoid arthritis (RA) and of degenerative bone conditions.…”

Section: Introductionmentioning

confidence: 99%

FGF2 induces RANKL gene expression as well as IL1β regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells

et al. 2013

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ObjectiveHuman bone marrow mesenchymal stromal cells (hBM-MSC) are being applied in tissue regeneration and treatment of autoimmune diseases (AD). Their cellular and immunophenotype depend on isolation and culture conditions which may influence their therapeutic application and reflect their in vivo biological functions. We have further characterised the phenotype induced by fibroblast growth factor 2 (FGF2) on healthy donor hBM-MSC focusing on the osteoimmunological markers osteoprotegerin (OPG), receptor activator of nuclear factor kB (RANK), RANK ligand (RANKL) and HLA-DR and their regulation of expression by the inflammatory cytokines IL1β and IFNγ.MethodsRANK, RANKL, OPG and HLA-DR expression in hBM-MSC expanded under specific culture conditions, were measured by RT-PCR and flow cytometry. MAPKs induction by FGF2, IL1β and IFNγ in hBM-MSC was analysed by immunoblotting and RT-PCR.ResultsIn hBM-MSC, OPG expression is constitutive and FGF2 independent. RANKL expression depends on FGF2 and ERK1/2 activation. IL1β and IFNγ activate ERK1/2 but fail to induce RANKL. Only IL1β induces P38MAPK. The previously described HLA-DR induced by FGF2 through ERK1/2 on hBM-MSC, is suppressed by IL1β through inhibition of CIITA transcription. HLA-DR induced by IFNγ is not affected by IL1β in hBM-MSC, but is suppressed in articular chondrocytes and lung fibroblasts.ConclusionsRANKL expression and IL1β regulated MHC-class II, both induced via activation of the ERK1/2 signalling pathway, are specific for progenitor hBM-MSC expanded in the presence of FGF2. HLA-DR regulated by IL1β and ERK1/2 is observed on hBM-MSC during early expansion without FGF2 suggesting previous in vivo acquisition. Stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration.

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The role of bFGF on the ability of MSC to activate endogenous regenerative mechanisms in an ectopic bone formation model

Cited by 75 publications

References 38 publications

Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration

Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration

In Vivo Implanted Bone Marrow-Derived Mesenchymal Stem Cells Trigger a Cascade of Cellular Events Leading to the Formation of an Ectopic Bone Regenerative Niche

FGF2 induces RANKL gene expression as well as IL1β regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells

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