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Stem cells provide exciting mechanistic, therapeutic options for obesity-related diseases
WASHINGTON — Human stem cell-derived somatic and brain cells can provide insights into the mechanistic pathways of obesity and could lead to new therapeutics, according to a presenter here.
In the opening keynote presentation at ObesityWeek, Rudolph L. Leibel, MD, director of the division of molecular genetics in the department of pediatrics and co-director of the Naomi Berrie Diabetes Center at the Institute of Human Nutrition at Columbia University, discussed the expanding field of using stem cells to determine the effect certain genetic mutations have on obesity and metabolic disorders.
Together with colleagues, Leidel has mapped, cloned and identified mutations in the genes controlling adiposity in rats, mice and humans. They have recently derived hypothalamic neurons from stem cells derived from human skin cells contributed by people with specific genotypes to explore the mechanisms behind certain obesity- and diabetes-related conditions, such as Bardet-Biedl and Prader-Willi syndromes.
Leibel and colleagues have identified candidate genes whose function is inactivated by severe mutations. The researchers can manipulate the stem cell-derived cell types to study how the genes are expressed and how they develop.
“We can take these cells and expose them to agents to see which, based on the mutation, might be helpful in terms of getting around mutations or otherwise altering the function downstream to rescue the phenotype, so to speak,” Leibel said. “This is a very interesting and growing use of stem cells to really recapitulate in vitro what otherwise we wouldn’t be able to, or hadn’t been able to, do with regard to human biology.”
In addition, these stem-cell derived cells can be used for in vivo models to study their development and function and potentially to test therapeutic agents.
To better understand the different genetic mechanisms for different etiologies of obesity, Leibel and colleagues are working toward developing hypothalamic organoids. Currently, organoids have been made for the cerebral cortex and for the arcuate nucleus of the hypothalamus using stem cells. The researchers are using single-cell sequencing to understand the transcriptional factors of the paraventricular nucleus of the hypothalamus. They will be able to use that knowledge to “recapitulate that developmental repertoire in stem cells to get [paraventricular nucleus of hypothalamus] neurons,” according to Leibel.
“This will give us a very important tool for being able to better understand many types of obesity but particularly Prader-Willi,” he said.
The final application discussed was the potential for stem cells in developing therapeutics. The stem cell-derived neurons can be used as cellular substrates for drug development.
Additionally, the derived cells are “true to the source,” according to Leibel, and therefore could plausibly be used for cell-replacement strategies, including using stem cell-derived beta cells to treat diabetes.
“This is new frontier with great promise and important bioethical implications,” Leibel concluded. – by Cassie Homer
Reference:
Leibel RL. Stem Cell-derived Hypothalamic Neurons in the Elucidation of the Pathogenesis of Human Obesity: A New Frontier. Presented at: ObesityWeek 2017; Oct. 29-Nov. 2, 2017; Washington, D.C.
Disclosure: Leibel reports no relevant financial disclosures.