To elucidate the mechanism of delta-to-beta cell trans-differentiation in zebrafish pancreas

Diabetes is one of the global epidemics, which afflicts more than 300 million people worldwide and its prevalence is rising at an alarming rate. Both Type 1 and Type 2 diabetes involve a decline in amount and function of the insulin-secreting pancreatic beta cells. The available drug treatments for diabetes can ameliorate the symptoms of the disease; however, they are ineffective in triggering the disease regression as they are incapable to restore beta cell function.

In this project, we are intrigued to identify the mechanism of trans-differentiation of non-beta cells into functional beta cells, using zebrafish as the model organism. Importantly, unlike other mammals, the zebrafish model is advantageous in that conditional genetic ablation of beta cells followed by the return of the beta cell mass can be imaged in the same animal with ease without any surgical intervention. Through single-cell classification of the adult zebrafish pancreas, we identified cells that express at the RNA and protein levels both insulin and somatostatin (sst1.1). In addition, pseudo temporal analysis using Monocle, revealed that these hybrid cells have an intermediate molecular makeup between beta and delta cells. Additionally, these hybrid/bi-hormonal cells represent 5-10% of the adult insulin-expressing population but surge in numbers following beta cell injury and during regeneration. Recently, using a genetic reporter line and in vivo live imaging studies, we found that delta cells respond rapidly to beta cell injury by changing their cell shapes (long cell protrusions, similar to delta cells, were observed in these hybrid cells) and upregulating the expression of insulin (within two days) following beta cell destruction, suggesting that they initiate a trans-differentiation process.

Using high resolution live imaging and beta cell ablation studies, we intend to study the source and functionality of the newly regenerated beta cells. Moreover, using state-of-the-art reporters of glucose-stimulated Calcium influx, we will assess the maturation of the de novo generated beta cells and the dynamics of their integration into functional islet networks.

Learning how to enhance or induce the intrinsic regenerative ability of the endocrine islets will have a profound implication for developing therapeutic treatments. Due to the beta cells limited ability to self-replicate, beta cell regeneration from the non-beta cell pool and pancreatic progenitors could be a promising approach to recover lost beta cells.

Publications:

A multipurpose toolkit for teaching DSP in an undergraduate course. D. Joseph, P. Chawla, H. Chander, T.K. Rawat. Computer Applications in Engineering Education. 2017;25:530-541.

Incorporating motility in the motor: role of the hook protein family in regulating dynein motility. Biochemistry. D. Dwivedi*, P. Chawla*, M. Sharma. 2019;58:1026-1031.

Insights on β-cell regeneration from the zebrafish shoal: from generation of cells to functional integration. P. Chawla, L.F.D. Silva, N. Ninov. Curr Opin Physiol. 2020;14:27-34.