UF college of medicine office of research
The new approach combines stem cell-derived thymic and beta cells to explore and potentially prevent autoimmune attacks in diabetes.
By Manny Rea
Holger Russ, Ph.D., an associate professor in the Department of Pharmacology and Therapeutics, has been awarded a competitive grant from the NIH’s Human Islet Research Network (HIRN) for a project uncovering the earliest immune triggers of type 1 diabetes (T1D) using an innovative combination of stem cell-derived tissues and personalized immune system modeling. Titled, “Understanding thymic epithelial and hematopoietic stem cell-intrinsic immune abnormalities driving T1D in optimized HIS mouse models,” the work is part of the HIRN Consortium on Modeling Autoimmune Diabetes (HIRN-CMAD) and aims to understand, and ultimately prevent, this autoimmune disease.
Russ, who joined UF in 2023, is interested in the underlying causes and potential treatments for T1D, the autoimmune version of diabetes in which the immune system mistakenly attacks healthy beta cells in the pancreas. Those beta cells are responsible for producing insulin, which regulates the blood sugar levels for energy use in cells across the body. Without insulin, the body turns to fat for energy, producing ketones that can lead to life-threatening conditions.
uf college of medicine
Holger Russ, Ph.D.
This study puts these breakthroughs into practice by allowing researchers to study both sides of the T1D equation: the immune system and the beta cells it mistakenly targets.
The Russ Lab investigates the disease through two approaches: generating replacement cells via stem cell therapy and creating novel model systems, including humanized mice to simulate human immunity and pancreatic function within a living system.
In their stem cell therapy work, the team uses induced pluripotent stem cells (iPSCs), derived from adult patient tissue, cells that replicated rapidly and with the ability. To differentiated into any functional cell type of the human body. Russ’s lab was one of the first three research groups to successfully generate insulin-producing beta cells from iPSCs, offering a potential unlimited source of functional cells for cell replacement therapy.
They’ve also used iPSCs to create thymic cells which, key in early immune system development and the “education” of white blood cells that distinguish between self and foreign tissue. The lab has explored these cells’ relevance to T1D development.
“IPSCs have tremendous potential for regenerative medicine approaches,” Russ said.
This study puts these breakthroughs into practice by allowing researchers to study both sides of the T1D equation: the immune system and the beta cells it mistakenly targets.
The lab will generate thymic cells from both healthy controls and individuals with T1D to determine whether immune cell “education” is skewed toward autoreactivity. In T1D, this process may be impaired in T1S, and immune cells begin targeting the body’s own tissues.
The team will also integrate iPSC-derived beta cells into personalized immune mouse models to directly observe how human immune systems respond. This will be the first model system to incorporate genetically matched, or isogenic, human thymic and beta cells into a live mouse.
“Humanizing these mouse models using stem cell-derived cells will create a highly personalized and realistic environment to understand how insulin producting beta cells are attacked and destroyed,” Russ said.
The HIRN grant, part of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), will support Russ’s work in cell differentiation, while collaborators, Drs. Megan Sykes and Remi Creusot at Columbia University will lead development of the humanized mouse models.
“This will be a great way to interrogate basic disease mechanisms, but to also later test ideas we have for T1D prevention,” he said. “The work has the potential to significantly advance our knowledge how and why T1D develops in humans, as we still don’t know the acute triggers of the disease. And if the field attains a better understanding, it will lead to the development of new treatment modalities and indicate novel approaches to prevent T1D in patients at risk.”