| Title |
Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation
|
|---|---|
| Published in |
Diabetologia, July 2017
|
| DOI | 10.1007/s00125-017-4355-7 |
| Pubmed ID | |
| Authors |
Miljan Kuljanin, Gillian I. Bell, Stephen E. Sherman, Gilles A. Lajoie, David A. Hess |
| Abstract |
Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSC(R)) vs nonregenerative (MSC(NR)) capacity. Secreted proteins associated with islet regenerative function were identified using stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomics. To functionally validate the importance of active Wnt signalling, we stimulated the Wnt-signalling pathway in MSC(NR) samples during ex vivo expansion using glycogen synthase kinase 3 (GSK3) inhibition (CHIR99201), and the conditioned culture media (CM) generated was tested for the capacity to support cultured human islet cell survival and proliferation in vitro. MSC(R) showed increased secretion of proteins associated with cell growth, matrix remodelling, immunosuppressive and proangiogenic properties. In contrast, MSC(NR) uniquely secreted proteins known to promote inflammation and negatively regulate angiogenesis. Most notably, MSC(R) maintained Wnt signalling via Wnt5A/B (~2.5-fold increase) autocrine activity during ex vivo culture, while MSC(NR) repressed Wnt signalling via Dickkopf-related protein (DKK)1 (~2.5-fold increase) and DKK3 secretion. Inhibition of GSK3 activity in MSC(NR) samples increased the accumulation of nuclear β-catenin and generated CM that augmented beta cell survival (13% increases) and proliferation when exposed to cultured human islets. Maintenance of active Wnt signalling within human MSCs promotes the secretion of matricellular and proangiogenic proteins that formulate a niche for islet regeneration. |
X Demographics
The data shown below were collected from the profiles of 8 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Canada | 3 | 38% |
| France | 1 | 13% |
| United States | 1 | 13% |
| Unknown | 3 | 38% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 6 | 75% |
| Scientists | 2 | 25% |
Mendeley readers
The data shown below were compiled from readership statistics for 37 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 37 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 10 | 27% |
| Researcher | 5 | 14% |
| Student > Ph. D. Student | 4 | 11% |
| Student > Master | 2 | 5% |
| Student > Doctoral Student | 1 | 3% |
| Other | 3 | 8% |
| Unknown | 12 | 32% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 7 | 19% |
| Biochemistry, Genetics and Molecular Biology | 6 | 16% |
| Engineering | 4 | 11% |
| Agricultural and Biological Sciences | 3 | 8% |
| Immunology and Microbiology | 2 | 5% |
| Other | 1 | 3% |
| Unknown | 14 | 38% |
Attention Score in Context
This research output has an Altmetric Attention Score of 4. 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 23 June 2018.
All research outputs
#7,287,407
of 22,988,380 outputs
Outputs from Diabetologia
#2,819
of 5,085 outputs
Outputs of similar age
#115,007
of 312,508 outputs
Outputs of similar age from Diabetologia
#76
of 86 outputs
Altmetric has tracked 22,988,380 research outputs across all sources so far. This one has received more attention than most of these and is in the 67th percentile.
So far Altmetric has tracked 5,085 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 22.7. This one is in the 43rd percentile – i.e., 43% of its peers scored the same or lower than it.
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We're also able to compare this research output to 86 others from the same source and published within six weeks on either side of this one. This one is in the 11th percentile – i.e., 11% of its contemporaries scored the same or lower than it.