title: β-cell-mimetic designer cells provide closed-loop glycemic control.
abstract: Chronically deregulated blood-glucose concentrations in diabetes mellitus result from a loss of pancreatic insulin-producing β cells (type 1 diabetes, T1D) or from impaired insulin sensitivity of body cells and glucose-stimulated insulin release (type 2 diabetes, T2D). Here, we show that therapeutically applicable β-cell-mimetic designer cells can be established by minimal engineering of human cells. We achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. Implanted circuit-carrying cells corrected insulin deficiency and self-sufficiently abolished persistent hyperglycemia in T1D mice. Similarly, glucose-inducible glucagon-like peptide 1 transcription improved endogenous glucose-stimulated insulin release and glucose tolerance in T2D mice. These systems may enable a combination of diagnosis and treatment for diabetes mellitus therapy.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Mingqi
authors.initials: M
authors.lastname: Xie
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, 200241 Shanghai, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Ye
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institut Universitaire de Technologie, IUT, Département Génie Biologique, F-69622 Villeurbanne Cedex, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Charpin-El Hamri
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.|SIB-Swiss Institute of Bioinformatics, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Claude
authors.initials: C
authors.lastname: Lormeau
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Pratik
authors.initials: P
authors.lastname: Saxena
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland. fussenegger@bsse.ethz.ch joerg.stelling@bsse.ethz.ch.|SIB-Swiss Institute of Bioinformatics, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stelling
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland. fussenegger@bsse.ethz.ch joerg.stelling@bsse.ethz.ch.|University of Basel, Faculty of Science, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D000818:Animals; D032701:Biomimetics; D001786:Blood Glucose / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D060846:Cell Engineering; D003921:Diabetes Mellitus, Experimental / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy*; D052216:Glucagon-Like Peptide 1 / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000637:transplantation; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D001786:Blood Glucose; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D002118:Calcium