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In Vivo CaV3 Channe...
In Vivo CaV3 Channel Inhibition Promotes Maturation of Glucose-Dependent Ca2+ Signaling in Human iPSC-Islets
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- Zhao, KX (författare)
- Karolinska Institutet
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- Shi, Y (författare)
- Karolinska Institutet
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Yu, J (författare)
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Yu, LN (författare)
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Kohler, M (författare)
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Mael, A (författare)
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Kolton, A (författare)
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Joyce, T (författare)
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Odorico, J (författare)
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- Berggren, PO (författare)
- Karolinska Institutet
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Yang, SN (författare)
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(creator_code:org_t)
- 2023-03-07
- 2023
- Engelska.
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Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 11:3
- Relaterad länk:
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http://kipublication...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- CaV3 channels are ontogenetically downregulated with the maturation of certain electrically excitable cells, including pancreatic β cells. Abnormally exaggerated CaV3 channels drive the dedifferentiation of mature β cells. This led us to question whether excessive CaV3 channels, retained mistakenly in engineered human-induced pluripotent stem cell-derived islet (hiPSC-islet) cells, act as an obstacle to hiPSC-islet maturation. We addressed this question by using the anterior chamber of the eye (ACE) of immunodeficient mice as a site for recapitulation of in vivo hiPSC-islet maturation in combination with intravitreal drug infusion, intravital microimaging, measurements of cytoplasmic-free Ca2+ concentration ([Ca2+]i) and patch clamp analysis. We observed that the ACE is well suited for recapitulation, observation and intervention of hiPSC-islet maturation. Intriguingly, intraocular hiPSC-islet grafts, retrieved intact following intravitreal infusion of the CaV3 channel blocker NNC55-0396, exhibited decreased basal [Ca2+]i levels and increased glucose-stimulated [Ca2+]i responses. Insulin-expressing cells of these islet grafts indeed expressed the NNC55-0396 target CaV3 channels. Intraocular hiPSC-islets underwent satisfactory engraftment, vascularization and light scattering without being influenced by the intravitreally infused NNC55-0396. These data demonstrate that inhibiting CaV3 channels facilitates the maturation of glucose-activated Ca2+ signaling in hiPSC-islets, supporting the notion that excessive CaV3 channels as a developmental error impede the maturation of engineered hiPSC-islet insulin-expressing cells.
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Zhao, KX
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Shi, Y
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Yu, J
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Yu, LN
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Kohler, M
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Mael, A
-
visa fler...
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Kolton, A
-
Joyce, T
-
Odorico, J
-
Berggren, PO
-
Yang, SN
-
visa färre...
- Artiklar i publikationen
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Biomedicines
- Av lärosätet
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Karolinska Institutet