New thesis on the role of T-type calcium channels in human pancreatic β cell maturity

What's the main focus of your thesis?

My thesis focuses on the role of exaggerated T-type Ca²⁺ channels in disturbing the acquisition and preservation of the maturity of hiPSC-islet insulin-expressing cells and native human islet β cells.

Which are the most important results?

I have successfully established an experimental model for in vivo microimaging and intervening hiPSC-islet maturation and native human islet dedifferentiation by inserting human islets into the anterior chamber of the eye (ACE) of immune-compromised mice. I have also satisfactorily developed an approach to retrieving the intracameral islet grafts intact for ex vivo and in vitro assays.

My data show that hiPSC-islets are engrafted, vascularized and survive well on the iris of immune-compromised mice. They gradually increase their insulin-secretory granules and develop glucose-dependent [Ca²⁺]_i dynamics on the recipient iris, reflecting true and reliable in vivo maturation of hiPSC-islets. Importantly, inhibition of T-type Ca²⁺ channels markedly promotes the in vivo development of glucose-dependent [Ca²⁺]_i dynamics.

My results reveal that exaggeration of T-type Ca²⁺ channels by hyperglycemia in β cells within intracameral native human islet grafts downregulates β cell maturity by mediating excessive Ca²⁺ influx, inducing cytoplasmic Ca²⁺/CaN-dependent HSF1 retention and decreasing expressing of the key exocytotic protein VAMP-2.

How can this new knowledge contribute to the improvement of people’s health?

My thesis demonstrates that abnormally upregulated β cell T-type Ca²⁺ channels hinder naïve human β cell maturation and dampen native human β cell maturity. These findings pinpoint pharmacological intervention of T-type Ca²⁺ channels as a promising strategy to counteract these two detrimental events and thus will be likely to facilitate the engineering of clinically transplantable hiPSC-islets and enhance the efficacy of diabetes treatment.

What are your future ambitions? 

I would like to continue my research on roles of T-type Ca²⁺ channels in β cell dedifferentiation and maturation and dedicate myself to translation of the acquired knowledge into diabetes treatments. Hopefully, my efforts will result in some novel therapies based on roles of T-type Ca²⁺ channels in β cell dedifferentiation and maturation.

Dissertation

Friday December 15, 2023 at 09:00 Rehabsalen Norrbacka

Thesis

The role of T-type calcium channels in human pancreatic β cell maturity