Growth Factor Activates Stem Cells and Regenerates Insulin-producing Cells

Diabetes Research Institute scientists found that BMP-7 mobilizes pancreatic stem-like cells to become new, insulin-producing cells.

Using a groundbreaking method to culture live sections of the pancreas for nearly two weeks, scientists from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine have charted the first dynamic single-cell map of the pancreas’ regenerative pathways.

The results, published in the journal Cell Metabolism, indicate that a growth factor termed BMP-7 fuels pancreatic stem-like cells (progenitors), mobilizing them from the ducts where they reside and pushing them to become new insulin-producing cells (islet beta cells). 

Researchers Work with Live Pancreas Sections

Pancreatic slices are thin, live sections that preserve the cellular architecture and cell-to-cell interactions of the native organ. DRI scientists had previously fashioned the conditions to culture them long-term, enabling the study of the organ’s regenerative ability in real time.

Juan Domínguez-Bendala, Ph.D., in his laboratory
Study principal investigator Juan Domínguez-Bendala, Ph.D., and team found that progenitor cells can regenerate islet beta cells.

This study goes one step further by applying a technology (single-cell RNA sequencing, or scRNA-seq) that allows for the sequencing of thousands of genes that are expressed in each cell that comprise a slice. Sequencing slices at different time points, in the presence or absence of BMP-7, led to the first-ever dynamic analysis of pancreatic regeneration.

“This analysis takes the shape of single-cell maps where different cell types are grouped into continents and countries,” said Juan Domínguez-Bendala, Ph.D., professor of surgery, director of the Pancreatic Regeneration and Stem Cell laboratory, and principal investigator of this work. “scRNA-seq analyses had previously suggested that progenitors may be able to become insulin-producing cells, but it was nothing more than a prediction. Looking at how single-cell maps of pancreatic slices from the same donor evolve with time, with or without BMP-7, took out all the guesswork and confirmed that progenitor cells do leave their country and ‘migrate across the ocean’ to regenerate islet beta cells elsewhere.” 

Catalyzing Pancreas Regeneration

The pancreas has a surprising repertoire of mechanisms to replenish damaged cells, ranging from the duplication of pre-existing cells to the conversion of some cell types into others as they are needed.

The DRI research suggests that BMP-7 taps into the reactivation of the very program that gave rise to the pancreas during embryonic development. But this wasn’t enough for the DRI investigators.

“What good would our discovery be if this regeneration mechanism is disabled in patients with type 1 diabetes?” asked Ricardo Pastori, Ph.D., professor of medicine, immunology, and microbiology, director of the Molecular Biology Laboratory, and co-principal investigator of this study.

Investigating BMP-7 for Patients with Type 1 Diabetes

To investigate whether this is the case, the Network of Pancreatic Organ Donors with Diabetes (nPOD) sent their most precious samples: live pancreatic slices from donors with type 1 diabetes.

Juan Dominguez-Bendala, Ph.D., at the microscope, and Ricardo Pastori, Ph.D., looking on.
Juan Dominguez-Bendala, Ph.D. (at the microscope), and Ricardo Pastori, Ph.D., found that BMP signaling remained intact for patients with type 1 diabetes.

Using a novel strategy during which slices are infected with viruses that can tag live, insulin-producing cells as they appear, the researchers showed that BMP-7-like molecules were able to induce the formation of new beta cells with the ability to secrete insulin in response to glucose stimulation.

“This is the true measure of beta cell functionality, and our results confirm that the regeneration pathways activated by BMP signaling remain intact in patients with type 1 diabetes,” said Dr. Pastori. 

“We have cured diabetes in dozens of different ways in mice and none have worked in humans so far, so it is understandable that some people may be desensitized to the impact of some of these advances,” added Dr. Domínguez-Bendala. “But to bring back the beta cells in a real, live piece of the pancreas of a donor with type 1 diabetes? It doesn’t get much more promising than that.”

These findings will be the basis for the development of pharmacological interventions to harness and speed up the natural ability of the pancreas to restore its own beta cells, bringing new hope to millions of patients with type 1 diabetes.

Tags: diabetes, Diabetes Research Institute, Dr. Juan Dominguez-Bendala, Ricardo Pastori