dc.contributor.advisor | Rajagopal, Jayaraj | |
dc.contributor.author | Rosado-Olivieri, Edwin | |
dc.date.accessioned | 2019-12-11T10:00:08Z | |
dc.date.created | 2019-11 | |
dc.date.issued | 2019-09-10 | |
dc.date.submitted | 2019 | |
dc.identifier.citation | Rosado-Olivieri, Edwin. 2019. In Vitro Modeling of Human β Cell Differentiation, Regeneration and Function. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. | |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:42013108 | * |
dc.description.abstract | Stem cell-derived β cells offer an inexhaustible source of functional β cells for cell therapy and disease modeling for diabetes. We capitalize on the in vitro differentiation of β cells as a model of human development to identify regulators of cell fate. Our analysis identified YAP, an effector of the Hippo pathway, as a factor critical for the differentiation of multipotent pancreatic progenitors. Its downregulation in progenitors promotes cell cycle exit and endocrine differentiation in vitro. We further show evidence for the utility of a YAP inhibitor to enhance the differentiation of glucose-responsive β cells. Our analysis also indicated that YAP re-activation in β cells promotes cell cycle re-entry, a process essential for the control of β cell mass. To identify novel regulators of β cell proliferation, we performed single cell RNA-sequencing of YAP-overexpressing β cells. This led to the identification of a LIF-responsive subpopulation of β cells that can be expanded in vitro and in vivo. Our work also delineated downstream gene regulatory networks that control β cell replication. Finally, we developed a technology to discover novel hormones expressed in β cells. We identified an uncharacterized gene, ER-seq08, that reduces blood glucose levels in vivo in an insulin-independent manner. Our work suggests that this axis may represent a second system by which β cells regulate glucose metabolism. In all, our work highlights the potential of using in vitro-derived β cells for the study of human development, regeneration and function. | |
dc.description.sponsorship | Medical Sciences | |
dc.format.mimetype | application/pdf | |
dc.language.iso | en | |
dash.license | LAA | |
dc.subject | stem cells | |
dc.subject | beta cells | |
dc.subject | diabetes | |
dc.subject | developmental biology | |
dc.subject | organ regeneration | |
dc.title | In Vitro Modeling of Human β Cell Differentiation, Regeneration and Function | |
dc.type | Thesis or Dissertation | |
dash.depositing.author | Rosado-Olivieri, Edwin | |
dc.date.available | 2019-12-11T10:00:08Z | |
thesis.degree.date | 2019 | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.grantor | Graduate School of Arts & Sciences | |
thesis.degree.level | Doctoral | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Doctor of Philosophy | |
thesis.degree.name | Doctor of Philosophy | |
dc.contributor.committeeMember | Galloway, Jenna | |
dc.contributor.committeeMember | Hsu, Ya-Chieh | |
dc.contributor.committeeMember | Harlan, David | |
dc.type.material | text | |
thesis.degree.department | Medical Sciences | |
thesis.degree.department | Medical Sciences | |
dash.identifier.vireo | | |
dc.identifier.orcid | 0000-0003-4756-0956 | |
dash.author.email | erosadoolivieri@gmail.com | |