Pre-treated blood stem cells reverse type 1 diabetes in mice

autoimmune attack in type 1 diabetes
In type 1 diabetes, autoreactive T-cells (like the one in yellow) attack insulin-producing beta cells in the pancreas. What if blood stem cells could be taught to neutralize them? (Image: Andrea Panigada)

Type 1 diabetes is caused by an immune attack on the pancreatic beta cells that produce insulin. To curb the attack, some researchers have tried rebooting patients’ immune systems with an autologous bone-marrow transplant, infusing them with their own blood stem cells. But this method has had only partial success.

New research in today’s Science Translational Medicine suggests a reason why.

“We found that in diabetes, blood stem cells are defective, promoting inflammation and possibly leading to the onset of disease,” says Paolo Fiorina, MD, PhD, of Boston Children’s Hospital, senior investigator on the study.

But they also found that the defect can be fixed — by pre-treating the blood stem cells with small molecules or with gene therapy, to get them to make more of a protein called PD-L1.

In experiments, the treated stem cells homed to the pancreas and reversed hyperglycemia in diabetic mice, curing almost all of them of diabetes in the short term. One third maintained normal blood sugar levels for the duration of their lives.

Paolo Fiorina, MD, PhD, Boston Children's Hospital

In a dish, the modified blood stem cells curbed the autoimmune reaction in cells from both mice and humans.

“There’s really a reshaping of the immune system when you inject these cells,” says Fiorina, a researcher in the Division of Nephrology at Boston Children’s.

The powers of PD-L1

Fiorina, Moufida Ben Nasr, PhD, and colleagues began by using gene expression profiling to find out what proteins blood stem cells make. They discovered that blood stem cells from diabetic mice and humans have alterations in the network of genetic regulatory factors that control production of PD-L1, preventing it from being made even in the early stages of diabetes.

PD-L1 is a known immune “checkpoint” molecule. It binds to a receptor on the inflammatory T-cells that are activated in autoimmune reactions, causing these cells to die or become anergic (or inactive). In the new study, the researchers showed that PD-L1 has a potent anti-inflammatory effect in the context of type 1 diabetes.

cell-based therapy for type 1 diabetes
Andrea Panigada/Nancy Fliesler

When they introduced a healthy gene for PD-L1 into the stem cells, using a harmless virus as the carrier, the treated cells reversed diabetes in mice. Treating the cells with a “cocktail” of three small molecules — interferon beta, interferon gamma and polyinosinic-polycytidylic acid — achieved the same effect.

“We think resolution of PD-L1 deficiency may provide a novel therapeutic tool for the disease,” says Ben Nasr, the study’s first author.

Future directions

More study is needed to determine how long the effects of the cell therapy last and how often the treatment would need to be given.

But in the meantime, Fiorina and colleagues are collaborating with scientists from Fate Therapeutics (San Diego, Calif.) to optimize the small-molecule cocktail used to treat the blood stem cells. They have completed a pre-IND (investigational new drug) meeting with the FDA to support the launch of a clinical trial in type 1 diabetes.

“The beauty of this approach is the virtual lack of any adverse effects, since it would use the patients’ own cells,” says Fiorina.


The study was supported by EFSD/Sanofi European Research Programme, an American Heart Association (AHA) Grant-in-Aid and by Fate Therapeutics. Boston Children’s Hospital and Fate Therapeutics have filed intellectual property covering pre-treatment of blood stem cells for immunoregulation.

The study’s co-authors were Sara Tezza, Francesca D’Addio and Vera Usuelli of Boston Children’s Hospital’s Division of Nephrology; Chiara Mameli of Buzzi Children Hospital, Milan, Italy; Anna Maestroni of the International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, University of Milan; Domenico Corradi, Silvana Belletti and Gabriella Becchi of the University of Parma, Italy; Luca Albarello of Ospedale San Raffaele, Milan, Italy; Gian Paolo Fadini of the University of Padova, Italy; Christian Schuetz and James Markmann of Massachusetts General Hospital; Clive Wasserfall of the University of Florida, Gainesville; Leonard Zon of Boston Children’s Stem Cell Research Program; and Gian Vincenzo Zuccotti of the International Center for T1D, University of Milan, and Buzzi Children Hospital, Milan.