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, Roberta; UliviValentina,; ReverberiDaniele,; Sicco, Claudia Lo; DescalziFiorella,; CanceddaRanieri,

doi:10.1089/scd.2013.0313

Cited by 59 publications

(48 citation statements)

References 39 publications

(62 reference statements)

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“…Activation of nuclear factor‐κ‐light‐chain‐enhancer of activated B cells (NF‐κB) stimulates cyclooxygenase two COX2, which in turn increases production of PGE 2 . PGE 2 binds to its receptors on the macrophages, which subsequently increases IL‐10 secretion, regulates macrophage polarization, and reduces inflammation . Similar to those studies, our results also indicated that TNF‐α induced production of PGE 2 by the MSCs, which then led to a decrease in M1 macrophages and the M1‐produced cytokine, IL‐12, and also resulted in an increase in IL‐6 and the anti‐inflammatory factor, IL‐4.…”

Section: Discussionsupporting

confidence: 89%

Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect

Aktaş

Chamberlain

Saether

et al. 2016

Journal Orthopaedic Research

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Tendon healing is a complex coordinated series of events resulting in protracted recovery, limited regeneration, and scar formation. Mesenchymal stem cell (MSC) therapy has shown promise as a new technology to enhance soft tissue and bone healing. A challenge with MSC therapy involves the ability to consistently control the inflammatory response and subsequent healing. Previous studies suggest that preconditioning MSCs with inflammatory cytokines, such as IFN-γ, TNF-α, and IL-1β may accelerate cutaneous wound closure. The objective of this study was to therefore elucidate these effects in tendon. That is, the in vivo healing effects of TNF-α primed MSCs were studied using a rat Achilles segmental defect model. Rat Achilles tendons were subjected to a unilateral 3 mm segmental defect and repaired with either a PLG scaffold alone, MSC-seeded PLG scaffold, or TNF-α-primed MSC-seeded PLG scaffold. Achilles tendons were analyzed at 2 and 4 weeks post-injury. In vivo, MSCs, regardless of priming, increased IL-10 production and reduced the inflammatory factor, IL-1α. Primed MSCs reduced IL-12 production and the number of M1 macrophages, as well as increased the percent of M2 macrophages, and synthesis of the anti-inflammatory factor IL-4. Primed MSC treatment also increased the concentration of type I procollagen in the healing tissue and increased failure stress of the tendon 4 weeks post-injury. Taken together delivery of TNF-α primed MSCs via 3D PLG scaffold modulated macrophage polarization and cytokine production to further accentuate the more regenerative MSC-induced healing response. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:269-280, 2017.

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Section: Discussionsupporting

confidence: 89%

Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect

Aktaş

Chamberlain

Saether

et al. 2016

Journal Orthopaedic Research

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“…Contextually, their efficacy in the functional improvement of injured tissues was mostly related to a paracrine effect rather than a direct engraftment and differentiation . We have recently demonstrated that in an inflammatory environment as the one generated during the early phases of the wound healing process, MSC paracrine activity was significantly modulated promoting a functional switch of macrophages from a pro‐ to an anti‐inflammatory state, thus corroborating evidences showing that the mobilization of innate immune cells mediates the activation of regenerative processes .…”

Section: Introductionsupporting

confidence: 69%

“…An increasing number of literature reports indicate that MSCs possess the capacity to reduce inflammation and to promote tissue repair processes by their paracrine activity . In particular, it was recently reported that lipopolysaccharide preconditioning of umbilical cord‐MSCs increased the secretion of exosomes, responsible for the switch of macrophages to a M2‐like profile .…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization

Sicco

Reverberi

Balbi

et al. 2017

Stem Cells Translational Medicine

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457

359

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Mesenchymal Stem Cells (MSCs) are effective therapeutic agents enhancing the repair of injured tissues mostly through their paracrine activity. Increasing evidences show that besides the secretion of soluble molecules, the release of extracellular vesicles (EVs) represents an alternative mechanism adopted by MSCs. Since macrophages are essential contributors toward the resolution of inflammation, which has emerged as a finely orchestrated process, the aim of the present study was to carry out a detailed characterization of EVs released by human adipose derived‐MSCs to investigate their involvement as modulators of MSC anti‐inflammatory effects inducing macrophage polarization. The EV‐isolation method was based on repeated ultracentrifugations of the medium conditioned by MSC exposed to normoxic or hypoxic conditions (EVNormo and EVHypo). Both types of EVs were efficiently internalized by responding bone marrow‐derived macrophages, eliciting their switch from a M1 to a M2 phenotype. In vivo, following cardiotoxin‐induced skeletal muscle damage, EVNormo and EVHypo interacted with macrophages recruited during the initial inflammatory response. In injured and EV‐treated muscles, a downregulation of IL6 and the early marker of innate and classical activation Nos2 were concurrent to a significant upregulation of Arg1 and Ym1, late markers of alternative activation, as well as an increased percentage of infiltrating CD206pos cells. These effects, accompanied by an accelerated expression of the myogenic markers Pax7, MyoD, and eMyhc, were even greater following EVHypo administration. Collectively, these data indicate that MSC‐EVs possess effective anti‐inflammatory properties, making them potential therapeutic agents more handy and safe than MSCs. stem cells translational medicine 2017 Stem Cells Translational Medicine 2017;6:1018–1028

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“…14,15 Seeded MSCs were also found to enable gathering of the host's monocytes at the implantation site where they later differentiate into osteoclasts, but disappear themselves from the implantation site after 1-2 weeks. 16,17 In this work. a model of transgenic mice and genetically labeled cells with a double control (GFP(C)mice/scaffolds with GFP(¡)MSCs; GFP(¡)mice/scaffolds with GFP(C)MSCs; GFP(C) mice/scaffolds without any MSCs) has been used to study the involvement of allogeneic MSCs in tissue regeneration.…”

Section: Discussionmentioning

confidence: 96%

“…On the one hand, it has been suggested that seeded MSCs may be capable of releasing major growth factors, reducing the innate immune response and mobilizing the host's cells. [14][15][16][17] On the other hand, since these cells can differentiate into osteoblasts, they may contribute directly to the bone formation. Nevertheless, the in vivo results are still unclear despite many in vitro experiments that show excellent results concerning the expansion, proliferation, migration, viability and osteogenic differentiation of MSCs on different types of scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Study of the involvement of allogeneic MSCs in bone formation using the model of transgenic mice

Kuznetsova

Prodanets

Rodimova

et al. 2016

Cell Adhesion & Migration

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Mesenchymal stem cells (MSCs) are thought to be the most attractive type of cells for bone repair. However, much still remains unknown about MSCs and needs to be clarified before this treatment can be widely applied in the clinical practice. The purpose of this study was to establish the involvement of allogeneic MSCs in the bone formation in vivo, using a model of transgenic mice and genetically labeled cells. Polylactide scaffolds with hydroxyapatite obtained by surface selective laser sintering were used. The scaffolds were sterilized and individually seeded with MSCs from the bone marrow of 5-week-old GFP(C) transgenic C57/Bl6 or GFP(¡)C57/Bl6 mice. 4-mm-diameter critical-size defects were created on the calvarial bone of mice using a dental bur. Immediately after the generation of the cranial bone defects, the scaffolds with or without seeded cells were implanted into the injury sites. The cranial bones were harvested at either 6 or 12 weeks after the implantation. GFP(C) transgenic mice having scaffolds with unlabeled MSCs were used for the observation of the host cell migration into the scaffold. GFP(¡) mice having scaffolds with GFP(C) MSCs were used to assess the functioning of the seeded MSCs. The obtained data demonstrated that allogeneic MSCs were found on the scaffolds 6 and 12 weeks post-implantation. By week 12, a newly formed bone tissue from the seeded cells was observed, without an osteogenic predifferentiation. The host cells did not appear, and the control scaffolds without seeded cells remained empty. Besides, a possibility of vessel formation from seeded MSCs was shown, without a preliminary cell cultivation under controlled conditions.

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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

Cited by 59 publications

References 39 publications

Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect

Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Mediators of Anti-Inflammatory Effects: Endorsement of Macrophage Polarization

Study of the involvement of allogeneic MSCs in bone formation using the model of transgenic mice

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