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Reversing type 1 diabetes

Progenitor cells in the pancreas can be regenerated into beta cells in order to respond to glucose...


Scientists from the Diabetes Research Institute (DRI) at the University of Miami Miller School of Medicine have confirmed the existence of progenitor cells within the human pancreas that can be stimulated to develop into glucose-responsive beta cells. A progenitor cell is a cell similar to a stem cell (which is completely able to become any cell of the body), but progenitor cells have gone the first leap to differentiate into a "target" cell - in this case a pancreatic cell.

These significant findings, published in Cell Reports, open the door for developing regenerative cell therapies for type 1 diabetics. The discovery addresses a challenge that has stood in the way of a biological cure for diabetes for decades.

The notion that the pancreas harbors progenitor cells with the potential to regenerate islet cells has been hypothesized for decades, but never conclusively demonstrated. DRI scientists have now been able to identify their exact anatomic location and validated their proliferative potential and ability to turn into glucose-responsive beta cells.
"Our in-depth study of these pancreatic stem cells may help us tap into an endogenous cell supply 'bank' for beta cell regeneration purposes and, in the future, lead to therapeutic applications for people living with type 1 diabetes. Together with our previous findings using BMP-7 to stimulate their growth, we believe that we may be able to induce these stem cells to become functional islets."

Juan Dominguez-Bendala PhD, Director of Pancreatic Stem Cell Development for Translational Research, co-principal investigator of the study alongside Dr. Ricardo Pastori PhD, Director of Molecular Biology.

The DRI team previously reported that bone morphogenetic protein 7 (BMP-7), a naturally occurring growth factor already approved by the Food and Drug Administration (FDA) for clinical use, stimulates progenitor-like cells within cultured human non-endocrine pancreatic tissue.

In the most recent study, the researchers went on to demonstrate that those stem cells that respond to BMP-7 reside within the pancreatic ductal and glandular network of the organ. Additionally, the cells are characterized by the expression of PDX1 — a protein necessary for beta cell development, and ALK3 — a cell surface receptor that has been associated with the regeneration of multiple tissues.

Pancreasr
Image source the Hirshberg Foundation for Pancreatic Cancer


Using "molecular fishing" techniques, they were able to selectively extract the cells that expressed PDX1 and ALK3, grow them in a dish and demonstrate that they can proliferate in the presence of BMP-7 and later differentiate into beta cells. Together, the combined study results may help move researchers closer to developing regenerative cell therapies for type 1, and potentially type 2, diabetes.

In type 1 diabetes, the insulin-producing cells of the pancreas are mistakenly destroyed by the immune system, requiring patients to manage their blood sugar levels through a daily regimen of insulin therapy. In type 2 diabetes, patients are able to produce some insulin, but their beta cells may become dysfunctional over time. Islet transplantation has allowed some patients with type 1 diabetes to live without the need for insulin injections after receiving infusions of donor cells, however there are not enough cells to treat the millions of patients who can benefit.

So far, research efforts have focused primarily on creating more pancreatic cells for transplant from sources like embryonic (hESc), pluripotent (hPSc) and adult stem cells, and porcine (pig) islets, among others. A more efficient and potentially safer solution could lie in regenerating a patient's own insulin-producing cells, sidestepping the need to transplant donor tissue altogether and eliminating other immune-related roadblocks.
"The ability to offer regenerative medicine strategies to restore insulin production in the native pancreas could one day replace the need for transplantation of the pancreas or insulin-producing cells. In type 1 diabetes, this would require abrogation of autoimmunity to avoid immune destruction of the newly formed insulin producing cells. For this reason our current efforts are converging on immune tolerance induction without the need for life long anti-rejection drugs."

Camillo Ricordi MD, Director, Diabetes Research Institute; Stacy Joy Goodman Professor of Surgery.

Summary
Stem cell therapies are finally coming of age in the context of pancreatic endocrine regeneration for diabetes. Clinical trials aimed at testing the safety and efficacy of human embryonic stem cell-derived islet surrogates are already ongoing.

If successful, these approaches are expected to lead to the phasing out of the use of cadaveric islets for transplantation, exponentially extending our ability to treat millions of type 1 diabetes – and potentially also type 2 diabetes – patients.

Different cell populations within the pancreas can regenerate the endocrine compartment through reprogramming, replication, or stimulation of resident progenitors.

The field has recently advanced to the point where these phenomena can be induced without the need for genetic manipulation, getting us closer to the design of viable clinical trials for ? cell replenishment or endogenous regeneration.

Islet transplantation is an effective cell therapy for type 1 diabetes (T1D) but its clinical application is limited due to shortage of donors. After a decade-long period of exploration of potential alternative cell sources, the field has only recently zeroed in on two of them as the most likely to replace islets. These are pluripotent stem cells (PSCs) (through directed differentiation) and pancreatic non-endocrine cells (through directed differentiation or reprogramming). Here we review progress in both areas, including the initiation of Phase I/II clinical trials using human embryonic stem cell (hESc)-derived progenitors, advances in hESc differentiation in vitro, novel insights on the developmental plasticity of the pancreas, and groundbreaking new approaches to induce ? cell conversion from the non-endocrine compartment without genetic manipulation.

Authors: Juan Domínguez-Bendala, Giacomo Lanzoni, Dagmar Klein, Silvia Álvarez-Cubela, Ricardo L. Pastor

About the Diabetes Research Institute
The Diabetes Research Institute at the University of Miami Miller School of Medicine leads the world in cure-focused research. As the largest and most comprehensive research center dedicated to curing diabetes, the DRI is aggressively working to develop a biological cure by restoring natural insulin production and normalizing blood sugar levels without imposing other risks. Researchers have already shown that transplanted islet cells allow patients to live without the need for insulin therapy. Some study participants have maintained insulin independence for more than 10 years. The DRI is now building upon these promising outcomes by developing a DRI BioHub, a bioengineered "mini organ" that mimics the native pancreas. While various BioHub platforms are being tested in preclinical and clinical studies, the DRI is also developing strategies to eliminate the need for anti-rejection drugs, reset the immune system to block autoimmunity, and develop and unlimited supply of insulin-producing cells. For more information, please visit DiabetesResearch.org, call 800-321-3437, or Tweet @Diabetes_DRI.


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Mar 5, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




Scientists confirm that progenitor cells are located within large ducts (GREEN) in the human pancreas. Above, are 2 such ducts surrounded by 3 islets (WHITE clusters of cells). Islet cells are also called islets of Langerhans, and are tiny clusters of cells scattered throughout the pancreas. The pancreas is an organ about the size of a hand and located behind the lower part of the stomach. Pancreatic islets contain several types of cells, including beta cells which produce the hormone insulin. The pancreas also makes enzymes that help digest and use food. Image: Diabetes Research Institute Foundation


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