幹細胞論壇

美國的生物研究沙克中心和加州聖地牙哥分校的團隊研究日前成功的從瑞特氏症(Rett syndorme)病人身上的皮膚細胞,誘導成多功能幹細胞(iPSC),再分化成自閉症(Autism)病人的神經細胞,如此可以研究造成病患神經細胞缺陷的致病機轉.

科學家藉由此方法發現,自閉症病人的腦神經細胞發生神經傳導的缺失,其突觸(synape)和樹突細胞(dentrite spine)漸漸減少,但其缺失是可逆的反應,因此燃起科學家的希望,認為自閉症是可以治療的疾病.此研究已發表在2010.11.12 的[細胞] (CELL) 期刊中.

蕾特氏症(Rett syndrome)是泛自閉症障礙(Autism spectrum disorders)最常見的一種神經系統的疾病，與基因異常(MeCP2 gene)有關。好發生於女孩，6-18個月時發展正常，18個月以後漸漸會出現病症，中後期會有發展遲滯，語言和智能上的障礙。

過去科學家只能利用電腦斷層掃描或是切片組織來研究自閉症的腦神經缺陷,如今能在實驗室中利用病患的多功能幹細胞衍生的神經細胞,更確切的得知自閉症障礙的病理機轉.

                  

科學家利用病患皮膚細胞->誘導成多功能幹細胞(iPSC)->分化出神經前驅細胞->再分化成神經細胞

左圖:正常人的神經細胞  右圖:蕾特氏症病人的神經細胞  紅色:神經突觸  綠色:神經樹突

 

Autism mimicked by cells in a dish

A collaborative effort between researchers at the Salk Institute for Biological Studies and the University of California, San Diego, successfully used human induced pluripotent stem (iPS) cells derived from patients with Rett syndrome to replicate autism in the lab and study the molecular pathogenesis of the disease. Their findings, published in the Nov. 12, 2010, issue of Cell, revealed disease-specific cellular defects, such as fewer functional connections between Rett neurons, and demonstrated that these symptoms are reversible, raising the hope that, one day, autism maybe turn into a treatable condition.

"Mental disease and particularly autism still carry the stigma of bad parenting," says lead author Alysson Muotri, Ph.D., an assistant professor in the Department of Molecular and Cellular Medicine at the University of California, San Diego School of Medicine. "We show very clearly that autism is a biological disease that is caused by a developmental defect directly affecting brain cells."

Rett syndrome is the most physically disabling of the autism spectrum disorders. Primarily affecting girls, the symptoms of Rett syndrome often become apparent just after they have learned to walk and say a few words. Then, the seemingly normal development slows down and eventually the infants regress, loosing speech and motor skills, developing stereotypical movements and autistic characteristics.

Almost all cases of the disease are caused by a single mutation in the MeCP2 gene, which is involved in the regulation of global gene expression, leading to a host of symptoms that can vary widely in their severity.

"Rett syndrome is sometimes considered a 'Rosetta Stone' that can help us to understand other developmental neurological disorders since it shares genetic links with other conditions such as autism and schizophrenia," says first author Carol Marchetto, Ph.D., a postdoctoral researcher in the Laboratory of Genetics at the Salk Institute.

In the past, scientists had been limited to study the brains of people with autistic spectrum disorders via imaging technologies or postmortem brain tissues. Now, the ability to obtain iPS cells from patients' skin cells, which can be encouraged to develop into the cell type damaged by the disease gives scientists an unprecedented view of autism.

"It is quite amazing that we can recapitulate a psychiatric disease in a Petri Dish," says lead author Fred Gage, Ph.D., a professor in the Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Diseases. "Being able to study Rett neurons in a dish allows us to identify subtle alterations in the functionality of the neuronal circuitry that we never had access to before."

Marchetto started with skin biopsies taken from four patients carrying four different mutations in the MeCP2 gene and a healthy control. By exposing the skin cells to four reprogramming factors, she turned back the clock, triggering the cells to look and act like embryonic stem cells. Known at this point as induced pluripotent stem cells, the Rett-derived cells were indistinguishable from their normal counterparts.

It was only after she had patiently coaxed the iPS cells to develop into fully functioning neurons—a process that can take up to several months—that she was able to discern differences between the two. Neurons carrying the MeCP2 mutations had smaller cell bodies, a reduced number of synapses and dendritic spines, specialized structures that enable cell-cell communication, as well as electrophysical defects, indicating that things start to go wrong early in development.

Since insulin-like growth factor 1 (IGF-1)—a hormone which, among other things, has a role in regulating cell growth and neuronal development—was able to reverse some of the symptoms of Rett syndrome in a mouse model of disease, the Salk researchers tested whether IGF-1 could restore proper function to human Rett neurons grown in culture.

"IGF-1 treatment increased the number of synapses and spines reverting the neuronal phenotype closer to normal," says Gage. "This suggests that the autistic phenotype is not permanent and could be, at least partially, reversible."

Muotri is particularly excited about the prospect of finding a drug treatment for Rett syndrome and other forms of autism: "We now know that we can use disease-specific iPS cells to recreate mental disorders and start looking for new drugs based on measurable molecular defects."