HSCI scientists show proof of concept that transplanted brown-fat-like cells can treat metabolic diseases
Harvard Stem Cell Institute scientists have developed a proof of concept for a novel cell-based therapy against obesity, the main cause of type 2 diabetes and related chronic illnesses. The potential therapy involves transplanting human brown-like fat cells, which are human white fat cells that have been genetically modified to become similar to heat-generating brown fat cells.
The study, led by Yu-Hua Tseng, Ph.D. at the Joslin Diabetes Center, is published in the journal Science Translational Medicine.
Brown fat cells burn energy instead of storing energy as white fat cells do. In the process, brown fat can lower excessive levels of glucose and lipids in the blood that are linked to metabolic diseases such as diabetes. People who are overweight or obese tend to have less of this beneficial brown fat.
To address this problem, the researchers took developmental-stage human white fat cells and used a gene editing technique to boost expression of a gene called UCP1, which triggered the white fat cell progenitors to develop into brown-fat-like cells.
Transplanted into mice lacking an immune system, the brown-fat-like cells developed into cells that functioned very much like the animals’ own brown fat cells.
The research team compared transplants of these cells versus the original white fat cells in mice that were put on a high fat diet. Mice given the cell transplants displayed a much greater sensitivity to insulin and ability to clear glucose from the blood, two key factors that are impaired in type 2 diabetes.
Additionally, the mice receiving the engineered cell transplants put on less weight than mice with transplanted white fat cells, and remained in the same range as animals that received brown fat cells.
These benefits were mostly due to signals from the transplanted cells to existing brown fat cells in the mice. “Cells in different tissues communicate with each other,” Tseng said. “In this case, we found that our transplanted cells secrete a molecule called nitric oxide, which is carried by red blood cells to the endogenous brown cells and activates those cells.”
If this technique continues to show success in pre-clinical research, it might be eventually possible to generate this type of cell for individual patients. Such a procedure would remove a tiny amount of a patient’s white fat cells, isolate the progenitor cells, modify those cells to boost expression of UCP1, and then return the resulting brown-fat-like cells to the patient.
However, that individualized approach could be complicated and expensive, so the researchers are pursuing two alternative routes that may be more practical for clinical use.
One alternative is to use cells that are not personalized, but instead are encapsulated via biomaterials that protect the cells from rejection by a patient’s immune system. The other approach is to develop a gene therapy that directly expresses the UCP1 gene in white fat progenitor cells in the body, so that those cells acquire brown-fat-like properties.
“Employing cell-based or gene therapies to treat obesity or type 2 diabetes used to be science fiction,” Tseng said. “Now scientific advances, such as CRISPR gene-editing technologies, will help us to improve the metabolism, the body weight, the quality of life, and the overall health of people with obesity and diabetes.”
This story was originally published on the Joslin Diabetes Center website on August 26, 2020, under the title “Transplanted brown-fat-like cells hold promise for obesity and diabetes.”
Source article: Wang, C.-H. et al. (2020). CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. Science Translational Medicine. DOI: 10.1126/scitranslmed.aaz8664
This study was supported by the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Department of Defense Congressionally Directed Medical Research Programs.