Without neurons reacting to the blood leptin level, the brain does not control the feeling of hunger and fullness. This type of genetic defects results in severe obesity in humans and animals. Scientists from Harvard University (HU), Massachusetts General Hospital (MGH) and the Nencki Institute of Experimental Biology of the Polish Academy of Sciences (Nencki Institute) in Warsaw have demonstrated in their experiments on mice that it is possible to restore brain functions by transplantation of small numbers of new neurons into the damaged area of the brain.
"A spectacular effect in the brain repair that we were able to achieve was significantly reduced weight of genetically defective obese mice and further significant reduction of adverse symptoms accompanying diabetes," says Dr. Artur Czupryn (Nencki Institute, HU, MGH), first author of a paper published in the latest issue of Science.
Already for some time medicine has attempted to repair damaged brain fragments through transplants of stem cells. These interventions are risky. Transplanted cells often develop in an uncontrolled manner, which frequently leads to cancer.
The aim of the research carried out for the past five years at HU, MGH and the Nencki Institute was to show that transplantation of small numbers of cells could restore the missing neuronal circuits and restore the lost brain functions. Genetically defective mice, deficient in leptin receptor, have been used in these experiments. Leptin is a protein secreted from cells of the fat tissue into the blood when eating. When it reaches the hypothalamus, it reacts with specific neurons and its presence or its low level cause the feeling of fullness or hunger, respectively. Leptin receptor deficient mice do not know the feeling of fullness. They weigh up to twice more than healthy individuals and suffer from advanced diabetes.
The team from Harvard University and Nencki Institute focused on the transplants of immature neurons (neuroblasts) and progenitors, which are specific stem cells with already determined developmental direction. Cells isolated from small regions of developing embryonic brains of healthy mice were used for transplantations. Thus, the probability increased that cells introduced into recipients' brains will transform into neurons or accompanying glial cells.
Millions of cells are usually transplanted. In this project, however, scientists injected a suspension of barely several thousand progenitors and neuroblasts into the hypothalamus of mice. About 300 nanolitres of cell suspension was injected into the mouse hypothalamus in the course of low invasive method -- by a thin micropipette with a diameter only several times larger than individual cells.
"The suspension was introduced into strictly defined region of the hypothalamus of mice, measuring about 200-400 micrometres in length. We were able to locate it thanks to unique high-frequency ultrasound microscopic guidance available at Harvard University. It allowed us to carry out complex non-invasive microtransplants with unprecedented precision, because we were able to carry out high resolution imaging of both the brain structures as well as the introduced micropipette," says Dr. Czupryn.
All transplanted cells have been marked with a fluorescent protein, which made possible to follow them in the recipients' brains. Observations carried out 20 or more weeks after the procedure have shown that almost half of transplanted cells transformed into neurons with typical morphology, producing proteins characteristic for normal neurons. By applying sophisticated research techniques, it was possible to demonstrate that the entire range of missing types of neurons was restored in the brain centre for controlling hunger and fullness. Moreover, the new neurons have already formed synapses and communicated with other neurons in the brain, as well as reacted properly to changes in levels of leptin, glucose, and insulin.
The final proof for restoration of proper functioning of the hypothalamus in mice was brought by measurements of body weight and blood metabolic factors. Unlike control population of genetically defective obese mice, the weight of mice with transplanted neurons resembled normal weight. Reversal of unfavourable changes of the blood metabolic parameters has also been observed.
"Many attempts have been described in the literature to date of transplanting cells into the brain. We have shown that a really small transplant of neuroblasts and progenitors was able to reconstitute damaged brain areas and influence the whole organism. We have shown that it is possible to introduce new neurons, which function properly, integrate well into the recipient nervous tissue and restore missing brain functions. Moreover this method turned out to be low invasive and safe, since it did not lead to tumour formation," sums up Dr. Czupryn.
Results achieved by the group from Harvard University and the Nencki Institute define a promising research direction, which could lead to the development of new repair therapies. This novel method could help, for example, eliminate the effects of stroke or improve the treatment of Parkinson's disease, which is associated with dysfunction within a defined brain area. Scientists emphasize however that long years of experiments, research, and tests are needed before therapies based on their ideas end up in the clinics and hospitals.
- A. Czupryn, Y.-D. Zhou, X. Chen, D. McNay, M. P. Anderson, J. S. Flier, J. D. Macklis. Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice. Science, 2011; 334 (6059): 1133 DOI: 10.1126/science.1209870
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