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The ACVR1 R206H mutation found in fibrodysplasia ossificans progressiva increases human induced pluripotent stem cell-derived endothelial cell formation and collagen production through BMP-mediated…

Overview of attention for article published in Stem Cell Research & Therapy, August 2016
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74 Mendeley
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Title
The ACVR1 R206H mutation found in fibrodysplasia ossificans progressiva increases human induced pluripotent stem cell-derived endothelial cell formation and collagen production through BMP-mediated SMAD1/5/8 signaling
Published in
Stem Cell Research & Therapy, August 2016
DOI 10.1186/s13287-016-0372-6
Pubmed ID
Authors

Emilie Barruet, Blanca M. Morales, Wint Lwin, Mark P. White, Christina V. Theodoris, Hannah Kim, Ashley Urrutia, Sarah Anne Wong, Deepak Srivastava, Edward C. Hsiao

Abstract

The Activin A and bone morphogenetic protein (BMP) pathways are critical regulators of the immune system and of bone formation. Inappropriate activation of these pathways, as in conditions of congenital heterotopic ossification, are thought to activate an osteogenic program in endothelial cells. However, if and how this occurs in human endothelial cells remains unclear. We used a new directed differentiation protocol to create human induced pluripotent stem cell (hiPSC)-derived endothelial cells (iECs) from patients with fibrodysplasia ossificans progressiva (FOP), a congenital disease of heterotopic ossification caused by an activating R206H mutation in the Activin A type I receptor (ACVR1). This strategy allowed the direct assay of the cell-autonomous effects of ACVR1 R206H in the endogenous locus without the use of transgenic expression. These cells were challenged with BMP or Activin A ligand, and tested for their ability to activate osteogenesis, extracellular matrix production, and differential downstream signaling in the BMP/Activin A pathways. We found that FOP iECs could form in conditions with low or absent BMP4. These conditions are not normally permissive in control cells. FOP iECs cultured in mineralization media showed increased alkaline phosphatase staining, suggesting formation of immature osteoblasts, but failed to show mature osteoblastic features. However, FOP iECs expressed more fibroblastic genes and Collagen 1/2 compared to control iECs, suggesting a mechanism for the tissue fibrosis seen in early heterotopic lesions. Finally, FOP iECs showed increased SMAD1/5/8 signaling upon BMP4 stimulation. Contrary to FOP hiPSCs, FOP iECs did not show a significant increase in SMAD1/5/8 phosphorylation upon Activin A stimulation, suggesting that the ACVR1 R206H mutation has a cell type-specific effect. In addition, we found that the expression of ACVR1 and type II receptors were different in hiPSCs and iECs, which could explain the cell type-specific SMAD signaling. Our results suggest that the ACVR1 R206H mutation may not directly increase the formation of mature chondrogenic or osteogenic cells by FOP iECs. Our results also show that BMP can induce endothelial cell dysfunction, increase expression of fibrogenic matrix proteins, and cause differential downstream signaling of the ACVR1 R206H mutation. This iPSC model provides new insight into how human endothelial cells may contribute to the pathogenesis of heterotopic ossification.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 74 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 74 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 14 19%
Student > Ph. D. Student 7 9%
Student > Master 7 9%
Student > Bachelor 7 9%
Other 5 7%
Other 17 23%
Unknown 17 23%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 20 27%
Agricultural and Biological Sciences 9 12%
Medicine and Dentistry 9 12%
Pharmacology, Toxicology and Pharmaceutical Science 7 9%
Immunology and Microbiology 4 5%
Other 6 8%
Unknown 19 26%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 August 2016.
All research outputs
#4,382,032
of 8,243,836 outputs
Outputs from Stem Cell Research & Therapy
#399
of 673 outputs
Outputs of similar age
#139,645
of 253,828 outputs
Outputs of similar age from Stem Cell Research & Therapy
#25
of 45 outputs
Altmetric has tracked 8,243,836 research outputs across all sources so far. This one is in the 27th percentile – i.e., 27% of other outputs scored the same or lower than it.
So far Altmetric has tracked 673 research outputs from this source. They receive a mean Attention Score of 5.0. This one is in the 28th percentile – i.e., 28% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 253,828 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 34th percentile – i.e., 34% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 45 others from the same source and published within six weeks on either side of this one. This one is in the 33rd percentile – i.e., 33% of its contemporaries scored the same or lower than it.