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Science publishes important findings by PKUBIO on Human Stem Cell Aging Mechanism

MAY . 13 2015
Peking University, May 13: A significant breakthrough on stem cell aging mechanism has been made by Fuchou Tang Lab from BIOPIC (Biodynamic Optical Imaging Center,Peking University), Guanghui Liu Lab from the Institute of Biophysics, Chinese Academy of Sciences and Juan Carlos Izpisua Belmonte Lab from the Salk Institution, by using pluripotent stem cell differentiation technology, targeted genome editing technology and epigenome analyzing techniques. The research has been published online by Science on April 30th, 2015, and for the very first time, uncovered a role for WRN in maintaining heterochromatin stability and highlighted heterochromatin disorganization as a potential determinant of human aging.

Nowadays, we are facing a world-wide population aging crisis, and roughly one third of China’s population will be over sixty in 2050. Aging is one of the most dangerous factors causing human diseases, and medical studies focusing on human and cell aging are receiving worldwide attention. Aging has become one of the most urgent and important issues. However, the process of aging is often long and complicated and it is impossible to find a model animal whose aging process bears enough resemblance to that of human being’s so that effective researches can be conducted. This proves to have created numerous challenges for translational medicine. Werner Syndrome is a rare autosomal recessive disorder, which is caused by a mutation on the WRN gene. Patients with the Werner Syndrome can develop premature aging, and are often accompanied by many senile diseases. Therefore, studying the Werner Syndrome can unveil the mystery of aging and help prevent senile diseases.

The researchers began by assuming that the aging of stem cells can lead to premature aging, and created the premature disordered MSC by developing a homozygous deletion on gene WRN in MSC (Mesenchymal Stem Cell). The premature disordered MSC showed various signs of aging, such as slow growth rate, increased DNA damage and large amount of proinflammatory cytokine excreting. The researchers have found substantial structure degeneration on the MSC’s heterochromatin, through histone modification, DNA methylation and whole genome scan on RNA transcript, which demonstrates as mountains deletion near H3K9me3 on telomeres and centromeres. And they also discovered that, WRN protein and the heterochromatin protein SUV39H1 and HP1a are found within the same protein complex, which sustains the stability of heterochromatin and nuclear lamina.

WRN deletion can cause the decreasing of the number of heterochromatin binding protein and of the transcription of centromere satellite DNA, which can induce the aging process. By comparing the vitro MSC from senior individuals with that of young individuals, it shows that the reconstruction of heterochromatin could be the main drive for aging of the normal cells. Finally, the overexpression of HP1a was proved to be an inhibitor of premature aging of cells.

This research, by using the model of the premature disordered MSC for the first time, uncovered the function of WRN protein in maintaining stability of the heterochromatin, illustrated the driving effect of chromatin architecture disorder on the cell aging, and concluded that human stem cell aging could result from the interaction between epigenetic mutations and genome instability.


Reported By: Lai Huan
Edited By: Xu Liangdi
Source:

PKU News (Chinese)

Science