Activin A marks a novel progenitor cell population during fracture healing and reveals a therapeutic strategy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA792499 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17333952.fastq.gz | Fastqsanger.gz | |||
| SRR17333953.fastq.gz | Fastqsanger.gz | |||
| SRR17333954.fastq.gz | Fastqsanger.gz | |||
| SRR17333955.fastq.gz | Fastqsanger.gz | |||
| SRR17333956_1.fastq.gz | Fastqsanger.gz |
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Project description:Bone fraction healing is effective in most individuals, but can be subpar and not easily treatable in patients such as the elderly, requiring new remedies. Here we tested whether activin A promotes fracture repair, inspired by recent studies showing that the protein stimulates ectopic bone formation in other systems. Using a standard mouse tibia fracture model, we found that activin A became very abundant in the developing callus soon after fracture. Single cell RNA-seq and immunostaining showed that initially, expression of the activin A-encoding gene Inhba characterized inflammatory cells and periosteal mesenchymal lineage cells. Over time, Inhba expression became prominent in a unique, highly-proliferative progenitor cell (PPC) population that displayed a myofibroblast character and was at the center of a developmental trajectory bifurcation toward cartilage and bone cells in callus. Systemic administration of a neutralizing activin A monoclonal antibody delayed fracture healing, whereas local implantation of recombinant activin A enhanced it. Cells engaged in healing produced phosphorylated SMAD2 through which activin A normally signals intracellularly, and were also positive for aSMA, a recognized marker of myofibroblasts. In vitro gain- and loss-of-function assays showed that activin A directly stimulated chondrogenesis, osteogenesis and myofibroblast differentiation in periosteal progenitors. Our study reveals that activin A is a positive regulator of fracture repair and may represent a new therapeutic tool to enhance it. Its action involves a prominent and transient PPC population with a myofibroblastic character that would rapidly gear up to bring about repair in a timely and effective manner.
2024-01-11 | GSE192630 | GEO
Project description:Genome-wide comparative gene expression analysis of callus tissue of osteoporotic mice (Col1a1-Krm2 and Lrp5-/-) and wild-type were performed to identify candidate genes that might be responsible for the impaired fracture healing observed in Col1a1-Krm2 and Lrp5-/- mice. To investigate bone healing in osteoporosis, we performed fracture healing studies in wild-type mice (C57BL/6 genetic background) and the low bone mass strains Col1a1-Krm2 and Lrp5-/- (Schulze et al., 2010; Kato et al., 2002). Osteotomy was set in femora of female mice and stabilized by a semi-rigid fixator to allow fast bone healing (RM-CM-6ntgen et al., 2010). 21 days post surgery we analyzed the fracture calli by biochemical/histological methods, as well as micro-computed tomography, and observed impaired fracture healing in Col1a1-Krm2 and Lrp5-/- mice in comparison to wild-type. To identify genes that may be responsible for the impaired healing in osteoporotic mice, we performed microarray analysis of three independent callus samples of each genotype. The callus tissue was taken 10 days after surgery, because extensive bone formation took place at this point.
2013-10-25 | E-GEOD-51686 | biostudies-arrayexpress
Project description:Rejuvenating Age-impaired Fracture Healing
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Project description:The association between DM and impaired fracture healing including delayed union and nonunion has been documented in clinical and experimental settings. We examine miRNA expression specific for impaired fracture healing in diabetic rat.
2017-01-15 | GSE76365 | GEO
Project description:The association between DM and impaired fracture healing including delayed union and nonunion has been documented in clinical and experimental settings. We examine mRNA expression specific for impaired fracture healing in diabetic rat.
2017-01-15 | GSE76364 | GEO
Project description:Fracture non-union is a complex clinical condition affecting many patients worldwide; however, known risk factors alone cannot help in predicting individual risk of progressing towards healing complications. The identification of novel biomarkers in the serum of fracture patients is crucial for early diagnosis and timely patient treatment. This study focused on the identification of microRNA (miRNA) that could correlate to the process of fracture healing. Toward this aim, serum of fracture patients and healthy volunteers was screened by RNA sequencing to identify differentially expressed miRNA at different times after injury. The results were correlated to miRNA that were found to be differentially secreted in the conditioned medium of human bone marrow mesenchymal stromal cells (BMSCs) during in vitro osteogenesis.
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Project description:Sprague-Dawley rats were placed on an ethanol-containing or pair-fed Lieber and DeCarli diets for 4 wks prior to surgical fracture. Following insertion of a medullary pin, a closed mid-diaphyseal fracture was induced using a Bonnarens and Einhorn fracture device. At 3 days post-fracture, the region of the fracture calluses were harvested from the right hind-limb. RNA was extracted and microarray analysis was conducted against the entire rat genome to study the effects of alcohol-consumption on the fracture healing. The experiments were on four rat subjects, i.e., pair-fed rats with subsequent surgical fracture or no surgical fracture, and alcohol-fed rats with subsequent surgical fracture or no surgical fracture. Each rat subject described above has three replicates so 6 kinds of pairing can be made and each pairing has a dye-swap replicate (thus, a total 12 array experiments). The focus of this study is on the pair-fed fracture subject vs. alcohol-fed fracture subject.
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Project description:Time-point expression analysis of fractures calluses at 1, 3, and 5 days post-fracture in young and old BALB/c mice. Femur fractures were generated on female c57BI6 mice in triplicate: 8 month old retired breeders (old mice) and 6 week old mice (young mice) were used. 1, 3, and 5 days post-fracture, fracture calluses were dissected and total RNA isolated. Expression profiling was performed using Affymetrix's Mouse Genome 430 2.0 array.
2009-09-01 | E-GEOD-17825 | biostudies-arrayexpress
Project description:Profiling of miRNA expressions comparing standard fracture healing models with nonunion models in rats 12w, male, Sprague–Dawley rats were used in this study. Animals were randomized to receive either a surgical treatment that has been shown to produce a nonunion or to a standard stabilized closed femoral shaft fracture that is known to successfully heal. The details of these procedures have been previously described. Briefly, to produce standard healing models, a 1.2-mm diameter K-wire was inserted retrograde into the right femoral intramedullary canal and a closed transverse femoral shaft fracture was produced using a three-point bending apparatus with a drop weight . To produce the nonunion, the fractured site was additionally exposed, and the periosteum was cauterized circumferentially for a distance of 2 mm on each side of the fracture . Five animals from each group were euthanized on post-fracture day 14 for microarray analysis.
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