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Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model.

ABSTRACT: Although activation of hedgehog (Hh) signaling has been shown to induce osteogenic differentiation in vitro and bone formation in vivo, the underlying mechanisms and the potential use of Hh-activated mesenchymal progenitors in bone defect repair remain elusive. In this study, we demonstrated that implantation of periosteal-derived mesenchymal progenitor cells (PDMPCs) that overexpressed an N-terminal sonic hedgehog peptide (ShhN) via an adenoviral vector (Ad-ShhN) restored periosteal bone collar formation in a 4-mm segmental bone allograft model in immunodeficient mice. Ad-ShhN enhanced donor cell survival and microvessel formation in collagen scaffold at 2 weeks after surgery and induced donor cell-dependent bone formation at 6 weeks after surgery. Fluorescence-activated cell sorting analysis further showed that Ad-ShhN-PDMPC-seeded scaffold contained a twofold more CD45(-)Sca-1(+)CD34(+)VEGFR2(+) endothelial progenitors than Ad-LacZ-PDMPC-seeded scaffold at day 7 after surgery. Ad-ShhN-transduced PDMPCs induced a 1.8-fold more CD31(+) microvessel formation than Ad-LacZ-transduced PDMPCs in a coculture of endothelial progenitors and PDMPCs. Taken together, our data show that overexpression of ShhN in mesenchymal progenitors improves bone defect reconstruction by enhancing donor progenitor cell survival, differentiation, and scaffold revascularization at the site of compromised periosteum. Hh agonist-based therapy, therefore, merits further investigation in tissue engineering-based applications aimed at enhancing bone defect repair and reconstruction.

SUBMITTER: Huang C

PROVIDER: S-EPMC3916037 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model.

Huang Chunlan C Tang Minghui M Yehling Eric E Zhang Xinping X

Molecular therapy : the journal of the American Society of Gene Therapy 20131003 2

Although activation of hedgehog (Hh) signaling has been shown to induce osteogenic differentiation in vitro and bone formation in vivo, the underlying mechanisms and the potential use of Hh-activated mesenchymal progenitors in bone defect repair remain elusive. In this study, we demonstrated that implantation of periosteal-derived mesenchymal progenitor cells (PDMPCs) that overexpressed an N-terminal sonic hedgehog peptide (ShhN) via an adenoviral vector (Ad-ShhN) restored periosteal bone collar ...[more]

PMID: 24089140

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Project description:Low levels of plasma adiponectin, an adipocytokine that possesses anti-inflammatory and antiatherogenic properties, frequently observed among obese subjects correlate with higher prevalence of several cardiovascular diseases. This study investigated whether adiponectin modulates allograft rejection in major histocompatibility complex class II-mismatched cardiac transplants.We heterotopically transplanted Bm12 allografts into adiponectin-deficient (APN-/-, C57BL/6 background) or wild-type (APN+/+) mice. Some APN-/- mice received adiponectin reconstitution by adenovirus. Histologic analyses assessed allograft rejection, and real-time reverse-transcriptase polymerase chain reaction evaluated the genes for cytokines/chemokines associated with the immune and inflammatory responses. In addition, we tested the effect of adiponectin on proliferation and cytokine/chemokine production in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.Allografts transplanted to APN-/- mice showed severe acute rejection relative to transplants in APN+/+ hosts accompanied by increased accumulation of CD4- and CD8-positive T lymphocytes and Mac3-positive macrophages. Adiponectin provision by adenovirus in APN-/- mice reversed these exacerbated responses to allografting. The rejected allografts in APN-/- mice contained significantly higher levels of tumor necrosis factor-alpha, interferon-gamma, and regulated on activation normal t expressed and presumably secreted. Moreover, adiponectin significantly suppressed proliferation and production of tumor necrosis factor-alpha, interferon-gamma, regulated on activation normal t expressed and presumably secreted, monocyte chemotactic protein-1, and interferon-gamma inducible protein-10 in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.These observations provide new mechanistic insight into immunoregulation in allograft recipients relative to obesity, an increasingly prevalent risk factor. Adiponectin may offer a new therapeutic target for allograft rejection after cardiac transplantation.

Dataset Information

Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model.

Publications

Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model.

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