1) Genetic control of functional maturation and de-differentiation

How does a newly formed stem or progenitor cell “knows” it has reached its full differentiation capacity, and should assume its mature function? What part of the signal towards terminal differentiation comes from the cell’s interactions with its surrounding environment, and what is encoded in the blueprint of its intrinsic developmental program? And how is the mature differentiation state, once achieved, is sustained throughout adult life, or tipped off balance and eroded in degenerative disease? These questions not only represent fundamental problems in developmental biology, but they are also crucial in regenerative medicine, where one wants to impose a functionally mature phenotype upon stem cells differentiated in vitro, or prevent the loss of the mature cell state in degenerative diseases.

We use the insulin secreting pancreatic β cells as our model system to study the genetic and molecular regulatory circuits controlling the development, maintenance, collapse and recovery of the fully differentiated, functionally mature cell state. We aim to be able to program naïve β cells differentiated from stem cells in vitro to produce and secrete exactly the right amount of insulin in response to a given concentration of glucose, and prevent de-differentiation and maintain functional β cell maturation in diabetics.

Schematic of beta-cell maturation and de-differentiation

2) The transcriptional landscape of beta cell maturation and de-differentiation (the Anna Karenina hypothesis)

All happy families resemble one another, each unhappy family is unhappy in its own way, writes Leo Tolstoy in the novel Anna Karenina. Our lab studies the Anna Karenina model of β cell de-differentiation in diabetes. Specifically, we investigate whether, in any type of diabetic stress, all de-differentiated β cells resemble one another, or if each type of diabetes produces β cells that are de-differentiated in their own unique way.

We do so by elucidating the transcriptional landscape and gene regulatory network changes during β cell differentiation in normal development, and their de-differentiation under various types diabetogenic stresses. We aim to distinguish between a model which predicts that de-differentiating β cells in diabetic mice resemble β cell progenitors, and a model in which β cell de-differentiation is not a reversal of ontogeny, but a simple loss of the mature β cell phenotype, and whether these are different in each type of diabetic stress. Distinguishing between these two models is critically important to finding ways to re-differentiate the de-differentiated β cells as means to restore glucose homeostasis in diabetics and to developing disease type-specific and patient-specific therapies for β cell failure in diabetes.

Anna Karenina proposed model

3) Organogenesis of the islets of Langerhans

A hallmark of diabetes is the loss of coordinated hormone secretion from the different cell types in the islets of Langerhans. Coordinated hormone secretion from the islet is enables by the islets’ unique three-dimensional organization and the precise ratios between its different cell types. Despite the critical importance of islet organization and cell type ratios to coordinated hormone secretion, and the strong role their loss plays in the development of diabetes, drags that target them as potential therapies to the disease have not yet been developed.

Stained control Islets with insulin in red and glucagon in green

To this end, we are studying the biological mechanism(s) that regulate islet organization, and endocrine cell type ratios and coordinated hormone secretion. Our goals are 1) to provide ways to prevent and restore the loss of islet organization, correct cell type ratios and coordinated hormone release in type-2 diabetics; 2) to provide ways to confer correct islet organization, correct cell type ratios and coordinated hormone release in human pluripotent stem cells-derived islet-like clusters in vitro, to generate an unlimited source of bona fide islets for transplantation, and 3) to inform bioengineering approaches for developing methods to support the structural integrity, survival and coordinated function of cadaver islets in clinical islet transplantation settings.