The critical role of Hedgehog-responsive mesenchymal progenitors in meniscus development and injury repair.
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ABSTRACT:
SUBMITTER: Wei Y
PROVIDER: S-EPMC8177886 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Stem cell therapy has potential for the treatment of degenerative meniscus injuries; however, an optimal animal model has not been established. Basic and clinical research show that synovial mesenchymal stem cells (MSCs) promote meniscus repair. The purposes of this study were to create a novel meniscus injury model in microminipigs and to investigate the effectiveness of synovial MSCs on meniscus healing in this model. The posterior portion of the medial meniscus in microminipigs was punctuated 200 times with a 23G needle. Allogenic synovial MSC suspension was placed on the injury site for 10 min for transplantation. The meniscus was evaluated histologically and via sagittal magnetic resonance imaging (MRI), radial MRI reconstructed in three dimensional, and T2 mapping at 1 and 8 weeks. Proteoglycan content stained with safranin-o disappeared 1 week after treatment in both the MSC and control groups but increased at 8 weeks only in the MSC group. Histological scores at 8 weeks were significantly higher in the MSC group than in the control group (n = 6). At 8 weeks, the T2 values of the MSC group were significantly closer to those of a normal meniscus than were those of the control group. High signal intensity areas of the MRIs and positive areas stained with picrosirius red coincided with meniscal lesions. In conclusion, we created a novel meniscus injury model in microminipigs. Evaluation via histology, MRIs, and polarized microscopy showed that transplantation of synovial MSCs improved meniscus healing.
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Project description:Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor β1 (TGFβ1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFβ1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.
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Project description:In recent years there has been increased attention on preserving the menisci because they perform vital roles in maintaining knee joint homeostasis. The anterolateral (AL) meniscal root is particularly vulnerable during anterior cruciate ligament reconstruction. When the AL root is iatrogenically injured, it is imperative that it is repaired in a timely fashion to prevent early-onset osteoarthritis. In this article we outline our knotless suture anchor repair for AL root tears.
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Project description:Improving outcomes in alcoholic liver disease (ALD) necessitates better understanding of how habitual ethanol (EtOH) consumption alters normal regenerative mechanisms within the liver. Hedgehog (Hh) pathway activation promotes expansion of progenitor populations in other tissues. We evaluated the hypothesis that chronic EtOH exposure activates Hh signaling in liver.Hh signaling, liver progenitors, transforming growth factor (TGF)-beta induction, and liver damage were compared in mice fed chow, high-fat diets (HF), or HF + EtOH for 4 weeks. Susceptibility to TGF-beta-mediated apoptosis was compared in Hh-responsive liver cells (eg, immature cholangiocytes and oval cells) and mature hepatocytes (which are unresponsive to Hh). Hepatic accumulation of Hh-responsive cells were compared in controls and ALD patients and correlated with a discriminant function (DF) that predicts subacute mortality.Hh signaling and numbers of Hh-responsive cells were increased in HF mice and greatest in HF+EtOH mice. In both, progenitor and stromal cell populations harbored Hh-responsive cells. More ductular-type progenitors and fibrosis markers were noted in HF+EtOH mice than in HF mice. The former also expressed more TGF-beta-1. TGF-beta-1 treatment selectively promoted the viability of Hh-responsive immature liver cells and caused mature hepatocytes that survived to produce Hh ligands. Hh-responsive cells were increased in ALD patients. Lobular accumulation of Hh-responsive immature ductular cells was greater in those with a DF >32 than those with a DF <32.Hh signaling is increased in ALD and may influence ALD outcomes by promoting hepatic accumulation of immature ductular cells.
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