Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration [bulk RNA-seq]

ABSTRACT: Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1mCherry and COL10A1eGFP double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249229 | GEO | 2024/09/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration [scRNA-seq]

Project description:Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1mCherry and COL10A1eGFP double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.

2024-09-30 | GSE271814 | GEO

Biomechanical and proteomic characterization of scaffold-free non-hypertrophic cartilage made of human adipose stem cell spheroids

Project description:Objective: We attempted to obtain a non-hypertrophic cartilage using ASC spheroids. In this study, several techniques were used to identify potential biomarkers of our in vitro model of chondrogenesis, supporting a phenotype of non-hypertrophic cartilage in induced ASC spheroids.

2022-03-03 | PXD009953 | Pride

Effect of electromagnetic fields on the chondrogenic differentiation under microgravity conditions

Project description:A combination therapy of electromagnetic fields (EMF) and simulated microgravity (SMG) has not been examined in regenerative medicine of cartilage. In the present study, a bioreactor system using extremely low-frequency EMF and SMG was applied during the chondrogenic differentiation of human mesenchymal stem cells (hMSCs). It was hypothesized that a beneficial effect of EMF regarding chondrogenesis (COL2A) could be combined with an avoiding effect of SMG regarding hypertrophy (COLXA1) of cartilage. Pellet cultures of hMSCs formed cartilaginous tissue under the addition of growth factors (FGF; TGF-Î²3). Pure SMG reduced COLXA1 expression but also COL2A expression of hMSCs. Pure EMF showed no gene expression changes of hMSCs during chondrogenic differentiation. Combining EMF/SMG resulted in a re-increase of COL2A but did not reach control levels. The COL2A to COLXA1 ratio of combined EMF/SMG was not significantly different from control levels. The combination therapy of EMF/SMG did not significantly improve the chondrogenic potential of hMSCs. chondrogenic differentiation, electromagnetic stimulation-control, 1 timepoint with/without stimulation

2015-12-31 | E-GEOD-57298 | biostudies-arrayexpress

Biomimetic strategy for cartilage formation: synergy of stem cell micro-aggregates and supramolecular peptide nanofibers

Project description:Recapitulation of embryonic developmental events is receiving increasing recognition as a strategy to induce robust tissue regeneration. In this work, we aimed to explore the critical events of cartilage formation by combining adult human bone marrow-derived mesenchymal stromal cells (hBMSCs) with supramolecular nanofibrous hydrogel. The micro-aggregation led to the altered global transcriptional profiles of hBMSCs and enhanced chondrogenic commitment early in 24h. Furthermore, the supramolecular nanofiber structure formed by peptide amphiphiles (PAs) maintained the cell cohesion and favored the deposition of cartilaginous matrix, thus facilitating the progression of differentiation. Upon subcutaneous implantation, the hBMSCs microaggregates-laden PA hydrogel demonstrated evident ectopic cartilage formation. Notably, RNA-sequencing data illustrated that the PA hydrogel facilitated the in vivo chondrogenesis progression of the encapsulated donor cells, and also activated the chondrogenesis in the host tissue via paracrine signaling. We conclude that PA hydrogel delivering microaggregates of hBMSCs could recapitulate the critical developmental events during cartilage development. This bioinspired approach will offer the potential to regenerate functional and durable tissues for the functional recovery of traumatic injuries of the cartilaginous skeleton .

2022-12-21 | GSE133727 | GEO

Effects of NGF and BDNF on chondrocytes

Project description:the objective of this study was to analyze the role of NGF and BDNF in the inflammatory process of OA and their effects on chondrogenesis, chondrocyte differentiation, cartilage degeneration and pain

2021-01-02 | GSE142823 | GEO

Effect of electromagnetic fields on the chondrogenic differentiation under microgravity conditions

Project description:A combination therapy of electromagnetic fields (EMF) and simulated microgravity (SMG) has not been examined in regenerative medicine of cartilage. In the present study, a bioreactor system using extremely low-frequency EMF and SMG was applied during the chondrogenic differentiation of human mesenchymal stem cells (hMSCs). It was hypothesized that a beneficial effect of EMF regarding chondrogenesis (COL2A) could be combined with an avoiding effect of SMG regarding hypertrophy (COLXA1) of cartilage. Pellet cultures of hMSCs formed cartilaginous tissue under the addition of growth factors (FGF; TGF-β3). Pure SMG reduced COLXA1 expression but also COL2A expression of hMSCs. Pure EMF showed no gene expression changes of hMSCs during chondrogenic differentiation. Combining EMF/SMG resulted in a re-increase of COL2A but did not reach control levels. The COL2A to COLXA1 ratio of combined EMF/SMG was not significantly different from control levels. The combination therapy of EMF/SMG did not significantly improve the chondrogenic potential of hMSCs.

2015-12-31 | GSE57298 | GEO

Mechanistic study comparing cartilage formation from human mesenchymal stromal cells and iPSC-derived multipotent cells [scRNA-seq]

Project description:Multipotent progenitor cells (iMPCs) created from induced pluripotent stem cells (iPSCs) is a promising cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) were shown to significantly enhance transforming growth factor-b (TGFb)-induced iMPC chondrogenesis. In contrast, TGFb alone is sufficient to induce robust chondrogenesis of human primary mesenchymal stromal cells (MSCs). Currently, the mechanism underlying this difference between iMPCs and MSCs has not been fully understood. In this study, we first generated iMPCs from human iPSCs and examined their differentiation capacity at different passages. We then optimized the conditions for chondrogenesis and determined that medium supplemented with TGFb and BMP6 led to robust cartilage formation from iMPCs with minimal hypertrophy. Moreover, the cartilage generated from this new method was resistant to osteogenic transition upon subcutaneous implantation and led to a hyaline cartilage-like regeneration in osteochondral defects in rats. Interestingly, TGFb alone induced phosphorylation of Smad2/3 in iMPCs but not Smad1/5, which led to poor chondrogenesis. In contrast, TGFb resulted in the phosphorylation of both Smad2/3 and Smad1/5 and robust chondrogenesis in human MSCs. We further discovered that the remarkably low level of Activin receptor-like kinase 1 (ACVRL1/ALK1) in iMPCs, when compared to MSCs, partially accounts for this difference. For instance, overexpression of ALK1 in iMPCs activated both Smad1/5 and Smad2/3 upon TGFb only treatment and resulted in a high level of chondrogenesis, which was not observed in control iMPCs. In summary, this study describes a robust method to generate chondrocytes with low hypertrophy for hyaline cartilage repair and elucidates the difference between MSCs and iMPCs in response to TGFb.

2022-12-20 | GSE197170 | GEO

Mechanistic study comparing cartilage formation from human mesenchymal stromal cells and iPSC-derived multipotent cells [bulk RNA-seq]

2022-12-20 | GSE197169 | GEO

Flightless I is a novel catabolic factor of chondrocytes that promotes hypertrophy and cartilage degeneration in osteoarthritis

Project description:Synovial macrophages that are activated by cartilage fragments initiate synovitis, a condition that promotes hypertrophic changes in chondrocytes leading to cartilage degeneration in OA. In this study, we analyzed the molecular response of chondrocytes under condition of this type of stimulation to identify a molecular therapeutic target. Stimulated macrophages promoted hypertrophic changes in chondrocytes resulting in production of matrix-degrading enzymes of cartilage. Among the top-upregulated genes, FliI was found to be released from activated chondrocytes and exerted autocrine/paracrine effects on chondrocytes leading to an increase in expression of catabolic and hypertrophic factors. Silencing FliI in stimulated cells significantly reduced expression of catabolic and hypertrophic factors in cocultured chondrocytes. Our further results demonstrated that the FliI-TLR4-ERK1/2 axis is involved in the hypertrophic signaling of chondrocytes and catabolism of cartilage. Our findings provide a new insight into the pathogenesis of OA and identify a potentially new molecular target for diagnostics and therapeutics.

2021-05-10 | GSE171420 | GEO

Gene expression profiling of the 414C2 iPSC line during hypertrophic chondrocyte induction

Project description:In order to better understand the mechanisms of chondrocyte hypertrophy, we induced hypertrophic chondrocytes from 414C2 iPSCs and analyzed their gene expression profile. This dataset includes the expression data obtained from iPSC-derived sclerotome and cartilage on days -1, 28, and 56 of induction. Day 56 samples were compared to day 28 samples to analyze pathways involved in chondrocyte hypertrophy.

2021-02-24 | GSE157955 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data