Researchers have for the first time successfully converted adult human skin cells into neurons of the type that regulate appetite, providing a patient-specific model for studying the neurophysiology of weight control and testing new therapies for obesity. The opensource study, led by researchers at Columbia University Medical Center (CUMC) and the New York Stem Cell Foundation (NYSCF), is published in the Journal of Clinical Investigation.
In previous studies the team have also succeeded in creating hypothalamic neurons from iPS cells. These neurons help to regulate behavioural and basic physiological functions in the human body, including, in addition to appetite, hypertension, sleep, mood, and some social disorders.
The team explain that mice are a good model for studying obesity in humans, but it would be better to have human cells for testing. Unfortunately, the cells that regulate appetite are located in an inaccessible part of the brain, the hypothalamus. So, until now, the medical community have had to make do with a mouse model or with human cells harvested at autopsy. This has greatly limited the ability to study fundamental aspects of human obesity.
To make the neurons, human skin cells were first genetically reprogrammed to become induced pluripotent stem (iPS) cells. Like natural stem cells, iPS cells are capable of developing into any kind of adult cell when given a specific set of molecular signals in a specific order. The iPS cell technology has been used to create a variety of adult human cell types, including insulin-producing beta cells and forebrain and motor neurons. But until now, no one has been able to figure out how to convert human iPS cells into hypothalamic neurons.
The team determined which signals are needed to transform iPS cells into arcuate hypothalamic neurons, a neuron subtype that regulates appetite. The transformation process took about 30 days. The neurons were found to display key functional properties of mouse arcuate hypothalamic neurons, including the ability to accurately process and secrete specific neuropeptides and to respond to metabolic signals such as insulin and leptin.
The team state that these neurons are not identical to natural hypothalamic neurons, but they are close and will still be useful for studying the neurophysiology of weight control, as well as molecular abnormalities that lead to obesity. In addition, the cells will allow the medical community to evaluate potential obesity drugs in a way never before possible.
The team summise that the findings show how improved understanding of stem cell biology is making an impact on the ability to study, understand, and eventually treat disorders of the nervous system. Because there are so few hypothalamic neurons of a given type, they have been notoriously difficult to study. The successful work by both groups shows that this problem has been cracked.
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