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Our work on pancreatic slices has just been published in the journal eLife. We show that the beta cells within the slice have fast calcium responses that drive enhanced insulin secretion. This demonstrates that the environment around beta cells is important for cell function.
In a recent review Kylie and I put forward a new model for the control of insulin secretion that draws mechanistic analogies with neurotransmitter release. Our review can be found here
We were involved in studying the beta cells from a patient in a collaboration with St Vincent’s in Melbourne. Our lab was able to show very unusual calcium responses, which together with other data showed that this patient had a specific defect in glucose metabolism. The work has been published here
Our work on human islets has just been published in Diabetologia. Here we show that human beta cells are polarised which is a breakthrough in understanding cell behaviour and could be important for the development of type 2 diabetes and in cell-based treatments for type 1 diabetes.
The work is a collaboration with clinicians at The Royal North Shore hospital in Sydney and at the islet transplant centres at Westmead and St Vincent’s.
Cottle L., Gan WJ., Gilroy I., Samra JS., Gill AJ., Loudovaris T., Thomas HE., Hawthorne WJ., Kebede MA. And Thorn P (2020) Structural and functional polarisation of human pancreatic beta cells in islets from organ donors with and without type 2 diabetes. Diabetologia. https://doi.org/10.1007/s00125-020-05345-8
In a multidisciplinary collaboration we show the benefit of coating an implant device with bioactive proteins. This coating enhances survival of cells within the implant and advances us towards a cell-based cure for type 1 diabetes.
Tan R, Hallahan N, Kosobrodova E, Michael P, Wei F, Santos M, Lam YT, Chan AHP, Xiao Y, Bilek MM, Thorn P, Wise SG. (2020) Bioactivation of encapsulation membrane reduced fibrosis and enhances cell survival. Applied Materials & Interfaces https://pubs.acs.org/doi/abs/10.1021/acsami.0c20096
In our first work using stem cells we show the benefit of growing the cells on extracellular matrix. This work builds on our understanding that native beta cells require extracellular matrix to function properly. It lays the rationale for future approaches to engineer new environments that better support cells within implants.
The work was funded in part by a generous donation from John and Anne Chong.
Singh R., Cottle L., Loudovaris T., Xiao D., Yang P., Thomas HE., Kebede MA. And Thorn P (2020) Enhanced Structure and Function of Human Pluripotent Stem Cell-Derived Beta-Cells Cultured on Extracellular Matrix. Stem Cells Translational Medicine. https://doi.org/10.1002/sctm.20-0224
Our collaborators in Melkam Kebede’s lab have just published in J Biol Chem work that begins to unravel the significance of granule aging in the control of insulin secretion.
Their paper:
Yau, B., Hays, L., Liang, C., Laybutt, D.R., Thomas, H.E., Gunton, J.E., Williams, L., Hawthorne, W.J., Thorn P., Rhodes, C.J.,and Kebede M.A. (2020) A fluorescent timer reporter enables sorting of insulin secretory granules by age. J Biol Chem 295(27):8901-8911
is highlighted as paper of the week:
https://www.jbc.org/content/295/27/8912.long
The actin cytoskeleton has been known to be involved in insulin secretion since the 1980s. In this paper we provide evidence for a mechanism that uses the actin nucleator, Arp2/3, to envelope each fusing insulin granule and control the release of insulin. We conclude that extremely local changes in actin are critical to beta cell function and secretory control.
Ma, W., Chang, J., Tong, J., Ho, U., Yau, B., Kebede, MA. And Thorn, P. (2020) Arp2/3 nucleates F-actin coating of fusing insulin granules in pancreatic beta cells to control insulin secretion. J Cell Sci 133 jcs236794
We have received funding from the Juvenile Diabetes Research Foundation to progress our research to design environments and cell culture conditions to optimise beta cell responses and insulin secretion.
The project will start when Covid conditions allow.
Congratulations to Ian Smyth and Dmitri Sviridov for their publication in EMBO Reports:
Ursino, GM., Fu, Y, Cottle, DL., Mukhamedova, N., Jones, LK., Low, H., Tham, MS., Gan, WJ., Mellet, NA., Das, PP., Weir, JM., Ditiatkovoski, M., Fynch, S., Thorn, P., Thomas, HE., Meikle, PJ., Parkington, HC., Smyth IM and Sviridov D. (2020) ABCA12 regulates insulin secretion from beta-cells EMBO Reps 21:e48692
We contributed to this paper by exploiting the assays we have developed to record granule fusion events in real time.