Abnormal Neural Progenitor Cells Differentiated from Induced Pluripotent Stem Cells Partially Mimicked Development of TSC2 Neurological Abnormalities.
Tuberous sclerosis complex (TSC) is a disease featuring devastating and therapeutically challenging neurological abnormalities. However, there is a lack of specific neural progenitor cell models for TSC. Here, the pathology of TSC was studied using primitive neural stem cells (pNSCs) from a patient presenting a c.1444-2A>C mutation in TSC2. We found that TSC2 pNSCs had higher proliferative activity and increased PAX6 expression compared with those of control pNSCs. Neurons differentiated from TSC2 pNSCs showed enlargement of the soma, perturbed neurite outgrowth, and abnormal connections among cells. TSC2 astrocytes had increased saturation density and higher proliferative activity. Moreover, the activity of the mTOR pathway was enhanced in pNSCs and induced in neurons and astrocytes. Thus, our results suggested that TSC2 heterozygosity caused neurological malformations in pNSCs, indicating that its heterozygosity might be sufficient for the development of neurological abnormalities in patients.
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China; Department of Neurology, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518017, P.R. China.
Yaqin
Y
Li
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China; Department of Neurology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, P.R. China.
Jiqing
J
Cao
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Menglong
M
Chen
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Jing
J
Li
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Yiming
Y
Sun
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Yu
Y
Zhang
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Yuling
Y
Zhu
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China.
Liang
L
Wang
Department of Neurology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China. Electronic address: zhangch6@mail.sysu.edu.cn.
Cheng
C
Zhang
D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D006579:Heterozygote; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
induced pluripotent stem cells; mTOR; neural differentiation; neurological abnormalities; primitive neural stem cells; tuberous sclerosis complex