Gli1+ progenitors mediate bone anabolic function of teriparatide via Hh and Igf signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA717012 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14062420_1.fastq.gz | Fastqsanger.gz | |||
| SRR14062420_2.fastq.gz | Fastqsanger.gz | |||
| SRR14062421_1.fastq.gz | Fastqsanger.gz | |||
| SRR14062421_2.fastq.gz | Fastqsanger.gz | |||
| SRR14062422_1.fastq.gz | Fastqsanger.gz |
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Project description:Teriparatide, a bioactive fragment of human parathyroid hormone (PTH), is the most widely prescribed bone anabolic drug in the world, but its cellular targets remain incompletely defined. The Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal growing mice, but their potential response to teriparatide is unknown. Here, by lineage tracing we find that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs. Single-cell RNA sequencing reveals heterogeneity among MMPs including a chondrocyte-like osteoprogenitor (herein COP) population that expands in response to teriparatide. COPs express the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor receptor Igf1r. Inhibition of Hh signaling, or selective deletion of Igf1r in MMPs diminishes the proliferative and osteogenic effects of teriparatide. The study therefore identifies MMPs as teriparatide target cells wherein Hh and Igf signaling are critical for osteoblast production.
2021-06-06 | GSE169560 | GEO
Project description:Teriparatide is the most widely prescribed bone anabolic drug in the world, but its cellular targets remain incompletely defined. The Gli1+ metaphyseal mesenchymal progenitors (MMPs) are a main source for osteoblasts in postnatal growing mice, but their potential response to teriparatide is unknown. Here, by lineage tracing, we show that teriparatide stimulates both proliferation and osteoblast differentiation of MMPs. Single-cell RNA sequencing reveals heterogeneity among MMPs, including an unexpected chondrocyte-like osteoprogenitor (COP). COP expresses the highest level of Hedgehog (Hh) target genes and the insulin-like growth factor 1 receptor (Igf1r) among all cell clusters. COP also expresses Pth1r and further upregulates Igf1r upon teriparatide treatment. Inhibition of Hh signaling or deletion of Igf1r from MMPs diminishes the proliferative and osteogenic effects of teriparatide. The study therefore identifies COP as a teriparatide target wherein Hh and insulin-like growth factor (Igf) signaling are critical for the osteoanabolic response in growing mice.
| S-EPMC8432334 | biostudies-literature
Project description:Inhibiting Hh signaling in Gli1+ osteogenic progenitors alleviates TMJOA
| PRJNA758561 | ENA
Project description:Attenuation of Hedgehog (Hh) pathway activity leads to increased prostate branching during adult prostate regeneration. In order to identify genes regulated by the Hh pathway that might be involved in adult prostate branching, we performed transcriptional profiling of regenerating prostates from wild-type or Gli1-/- mutant mice, which have attenuated Hh pathway activity. 6 total samples were analyzed. 3 wild-type prostates and 3 Gli-/- mutant prostates were analyzed.
2014-10-31 | E-GEOD-59849 | biostudies-arrayexpress
Project description:The goal of this study is to investigate the role of Gli1+ osteogenic progenitors in the development of TMJOA.
2021-11-04 | GSE182969 | GEO
Project description:Attenuation of Hedgehog (Hh) pathway activity leads to increased prostate branching during adult prostate regeneration. In order to identify genes regulated by the Hh pathway that might be involved in adult prostate branching, we performed transcriptional profiling of regenerating prostates from wild-type or Gli1-/- mutant mice, which have attenuated Hh pathway activity.
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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a highly malignant pediatric leukemia, where few therapeutic options are available for patients which relapse. The evolutionarily conserved Hedgehog (Hh) pathway plays a crucial role in patterning and organogenesis during early development, in adult tissue maintenance and repairing functions. Once Hh ligands bind to PTCH1/2 on target cells, the inhibition of Patched proteins for Smo is relieved. Smo translocates to the primary cilium and leads to the breakdown of a protein complex formed by Suppressor of Fused (SUFU) and GLI proteins. GLI transcription factors (GLI1-3) are released and translocate to the nucleus, initiating transcription of Hh target genes. GLI2 and GLI3 have transcriptional activation and repression properties, while GLI1 is a strong positive regulator of Hh transcriptional targets. In T-ALL rare hedgehog pathway mutations have been observed and approximately 20% of T-ALL cases present with ectopic expression of Hh pathway ligands and GLI1. However, the function of Hh signaling and in particular GLI transcription factors in T-ALL initiation and/or tumor progression is not well-known. RNA sequencing was performed in the CUTLL1 T-ALL cell line after knocking out GLI1 gene using CRISPR/Cas9 system.
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Project description:To assess if Hedgehog (Hh) responding cells in the skin have a unique expression profile, isolated keratinocytes that express the Hh response gene Gli1 were collected by FACS and their gene expression was compared to sorted CD34-expressing cells from the middle bulge region of the hair follicle and to cells from the interfollicular epidermis (IFE) by hybridization of isolated RNA to gene expression microarrays. Dissociated keratinocytes isolated form back skin of Gli1-eGFP/+ mice (2 mice pooled for each replicate) in adult telogen were sorted based on GFP expression and immunostaining for CD34. Only viable, single cells with immunostaining for α6 Integrin (to mark basal keratinocytes) were collected. GFP(+) cells were collected as the Gli1 cohort. GFP(-) CD34(+) cells were collected as the CD34 cohort, and GFP(-) CD34(-) cells were collected as interfollicular epidermis (IFE) cohort. Total RNA was extracted from each cell population and labeled for hybridization to gene expression microarrays. The experiment was preformed in triplicate, however RNA from the Gli1(+) cells in one replicate was of insufficient quality to analyze. For staining of isolated keratinocytes, cells were incubated on ice for 1 hour in SMEM containing 1%BSA and 15μL of anti-CD49f-PE antibody (BDBioscience) plus 5μL anti-CD34-APC antibody (eBioscience) for each 100μL total volume for each 2 million cells. Immediately prior to sorting, DAPI (Invitrogen) was added to the washed cells at 1μg/mL final concentration.
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Project description:Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing, the etiology of which is unknown. Although keloids cause life inconveniences and cosmetic problems, the lack of animal models has yet to elucidate their pathogenesis or develop effective treatments. Here, we found that the characteristics of stem cells from keloid lesions and surrounding dermis differ from those of normal skin and that HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, HH-signal inhibitor vismodegib reduced keloid reconstituted tumor size and the expression of keloid related genes in nude mouse, and the collagen bundle and the expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic target of keloids.
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Project description:Keloids are benign fibroproliferative skin tumors caused by aberrant wound healing, the etiology of which is unknown. Although keloids cause life inconveniences and cosmetic problems, the lack of animal models has yet to elucidate their pathogenesis or develop effective treatments. Here, we found that the characteristics of stem cells from keloid lesions and surrounding dermis differ from those of normal skin and that HEDGEHOG (HH) signal and its downstream transcription factor GLI1 were upregulated in keloid patient-derived stem cells. Inhibition of the HH-GLI1 pathway reduced the expression of genes involved in keloids and fibrosis-inducing cytokines, including osteopontin. Moreover, HH-signal inhibitor vismodegib reduced keloid reconstituted tumor size and the expression of keloid related genes in nude mouse, and the collagen bundle and the expression of cytokines characteristic for keloids in ex vivo culture of keloid tissues. These results implicate the HH-GLI1 pathway in keloid pathogenesis and suggest therapeutic target of keloids.
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