The high hopes of insulin-independence for patients with type 1 diabetes have been tempered by the limited availability and short-term function of transplanted human islets. The development of alternate sources of cells, through guided differentiation of stem cells or transdifferentiation of other mature cells, has therefore emerged as a viable prospect for diabetes cure. The low efficiency of achieving the cell phenotype has focused attention on factors that govern the pancreatic to endocrine progenitor developmental transition. We have determined that the concerted actions of Pdx1 and Oc1, two transcription factors expressed during this transition, contribute to formation and maturation of endocrine progenitors and their descendants in mice by directly regulating the proendocrine gene Ngn3 and by participating in a cross-regulatory transcriptional network. We hypothesize that Pdx1-Oc1 interaction drives induction of the endocrine pancreas gene program during normal development and in receptive progenitor cells. We test this hypothesis by (1) characterizing the genetic interaction between Pdx1 and Oc1 during embryonic development, (2) determining whether Pdx1 and Oc1 establish a permissive epigenetic landscape for activation of genes of the cell lineage, and (3) by determining whether combined Pdx1 and Oc1 gain of function can promote cell formation and function in vivo, in human pancreatic duct cells and in human embryonic stem cells. These studies make use of ex vivo and in vivo approaches using both mouse and human model systems. Successful completion of the proposed aims will reveal biochemical, epigenetic, and developmental mechanisms of action whereby Pdx1 and Oc1 cooperate to establish the endocrine and cell lineages. This information can be used in directed differentiation and transdifferentiation strategies to generate new fully functional cels from stem cells, progenitor cells, or other non- cells.

Public Health Relevance

Beta cell failure underlies the development of all forms of diabetes; however, the high hopes for cell replacement therapy have been tempered by the poor efficiency of generating the mature beta cell phenotype in efforts to guide differentiation or reprogramming of other cell types. We have identified two factors that work together to regulate the formation and maturation of beta cell progenitors. The information we generate may be useful to improve directed differentiation and reprogramming strategies to generate new fully functional cells from stem cells, progenitor cells, or other non- cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK105689-04
Application #
9606475
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sato, Sheryl M
Project Start
2015-12-22
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kropp, Peter A; Dunn, Jennifer C; Carboneau, Bethany A et al. (2018) Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability. Am J Physiol Endocrinol Metab 314:E308-E321
Stanescu, Diana E; Yu, Reynold; Won, Kyoung-Jae et al. (2017) Single cell transcriptomic profiling of mouse pancreatic progenitors. Physiol Genomics 49:105-114
Kropp, Peter A; Gannon, Maureen (2016) Onecut transcription factors in development and disease. Trends Dev Biol 9:43-57
Zhang, Yuxiang; Fang, Bin; Damle, Manashree et al. (2016) HNF6 and Rev-erb? integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev 30:1636-44
Henley, Kathryn D; Stanescu, Diana E; Kropp, Peter A et al. (2016) Threshold-Dependent Cooperativity of Pdx1 and Oc1 in Pancreatic Progenitors Establishes Competency for Endocrine Differentiation and ?-Cell Function. Cell Rep 15:2637-2650