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Genome Editing for Browning Human Fat Cells as a Potential Therapy for Type 2 Diabetes and Other Metabolic Diseases in the Czech & Corvera Labs

Researcher Spotlight: Emmanouela Tsagkaraki, MD, PhD

emmanouela-tsagkaraki-adipose-research — Emmanouela Tsagkaraki, MD, PhD, an Instructor in the Czech laboratory

Cell therapies have been successfully utilized to treat patients in oncology and other fields of medicine, and scientists at UMass Chan Medical School are investigating potential clinical applications for type 2 diabetes and obesity. Research in the laboratory of Michael Czech, PhD, includes investigating a novel approach to modify the response of human adipocyte (fat cells) genes to transcription factors using CRISPR genome editing. The Czech lab is collaborating with the laboratory of Silvia Corvera, MD, to explore a cell therapy approach by engineering the genome of human adipocyte promoters to expand their use in metabolic diseases such as diabetes and beyond.

A study published in Molecular Metabolism (2023) explored the relationship between a predominant protein and signaling pathway in adipocytes that each play an important role in regulating blood glucose metabolism and lipids.

Brown and beige adipose tissue burn fat and improves metabolism, as opposed to white adipose tissue which store fat. The Czech lab is testing ways to activate beige fat as a potential therapy for obesity and other metabolic diseases including type 2 diabetes.

Nuclear receptor-interacting protein 1 (NRIP1), also known as receptor-interacting protein 140 (RIP140), is a protein that is encoded by the NRIP1 gene in humans. When the RIP140 molecule was completely knocked out in fat tissue that was transplanted into mice, those animals remained lean.

Thermogenesis in fat tissue consists of many signaling pathways that are regulated by coding Ribonucleic acid (RNA). The Cyclic AMP pathway (cAMP) plays key roles in cellular responses to a variety of hormones and neurotransmitters.

The Czech lab also determined that knocking out NRIP1 helped the cAMP pathway mediate its effect on the beiging of adipocytes.

The Czech lab is collaborating with the laboratory of Silvia Corvera, MD, to explore a cell therapy by manipulating the genome of adipocytes to increase fat burning and improve the metabolic function of the cells.

“While white adipocytes store energy in the form of fat, we know that brown adipocytes do the opposite by helping to burn energy,” said Emmanouela Tsagkaraki, MD, PhD, an instructor in the Czech lab. “However, brown fat is not abundant in people with metabolic diseases such as type 2 diabetes, so we are editing genes to convert white fat cells into brown-like cells in an effort to enhance glucose metabolism.”

This works extended their 2021 study published Nature Communications for which Dr. Tsagkaraki led a team of scientists who removed cell samples from humans, converted white adipocytes into brown-like cells in the lab, reproduced and multiplied those cells, and transplanted them into specialized mice to test the therapeutic approach. Their data indicates the process enhanced and improved glucose metabolism. It showed that Nrip1 depletion in human adipose tissue provides a greater metabolic benefit when implanted in mice than untreated tissue. These new studies suggest that combining Nrip1 knockout in adipocytes with stimulation by cAMP stimulating agents may provide a further uptick in therapeutic benefit.

“These implanted cells could potentially provide brown-like cells to people who don’t otherwise have them, and provide beneficial systemic effects to their whole-body metabolism,” added Dr. Tsagkaraki. “I'm excited about the clinical potential. It’s promising that CRISPR-based cell therapies could treat a wide range of diseases including diabetes.”

CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease

Tsagkaraki E, Nicoloro SM, DeSouza T, Solivan-Rivera J, Desai A, Lifshitz LM, Shen Y, Kelly M, Guilherme A, Henriques F, Amrani N, Ibraheim R, Rodriguez TC, Luk K, Maitland S, Friedline RH, Tauer L, Hu X, Kim JK, Wolfe SA, Sontheimer EJ, Corvera S, Czech MP. Nat Commun. 2021 Nov 26;12(1):6931. doi: 10.1038/s41467-021-27190-y. PMID: 34836963

Department of Defense Funding

The collaborative research has been funded in part through the Department of Defense’s Partnering Principal Investigator Option. The grant continues through 2024 to fund pre-clinical studies in non-human primates.

In 2016, the Corvera Lab published in Nature Medicine, a method they developed to generate new human fat cells, particularly beneficial beige fat, from precursor cells present in white fat. When those cells were implanted in mice with diabetes, their metabolism improved.

The Czech Lab, in collaboration with the Sontheimer and Wolfe labs at UMass Chan, developed a novel way to deliver CRISPR/Cas9 ribonucleoprotein to fat cells. They degrade and disappear within hours after efficiently edit the DNA of fat cells. This method eliminates negative immune and toxic effects, making it safe for therapeutic applications.

About Dr. Tsagkaraki

Dr. Tsagkaraki was born and raised on the Greek island of Crete and earned her MD and MSc degrees from the University of Crete Medical School. Her goal is to pursue medical residency and become a physician-scientist. The “Molecular Basis of Human Diseases” graduate program in Greece “bridged the gap between clinical care and molecular medicine research.”

Drs. Czech and Corvera were visiting faculty members of her graduate program. They travel to Crete each year to give lectures and meet with students. “My major areas of interest have always been cell therapies and regenerative medicine,” said Dr. Tsagkaraki. “I never would have imagined these cutting-edge principals and approaches could be applied to the treatment of Type 2 diabetes until I attended their talks.”

Dr. Tsagkaraki joined the Czech Lab in 2017 to complete her master’s thesis and then began her PhD working on CRISPR/Cas9 genome engineering in adipocytes to improve metabolic activity and glucose homeostasis.

Adjusting to the United States was difficult at first. “Moving here at 25 years old and not knowing anybody was a challenge,” she said with a smile. “I was excited to be working at UMass but there was a learning curve to living in a new environment. It allowed me to learn a lot about myself and people on campus were very friendly and helpful.”

Her parents instilled in her that to become a successful scientist, one must experience different places, meet many people and hear varied points of view and perspectives. They both come from Polytechnic backgrounds. Her father is an engineer, and her mother is an architect. They raised her to understand the importance of investing in education, because “knowledge is something that cannot be taken away from you.”

Favorite Hobbies and Activities

Enjoys playing piano and singing
Performed with a choir in Greece, singing at festivals & events throughout Greece and Europe
Participated in math competitions growing up
Has traveled to most European countries and China. Looks forward to exploring the United States, India, Central America and more to learn about different cultures throughout the world
Loves swimming & windsurfing - grew up 20 minutes from “the sea”