Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities.
Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities.
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DOI：
10.1038/mp.2015.7
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发表时间：
2015-06
影响因子：
11
通讯作者：
Haggarty, S. J.
中科院分区：
文献类型：
--
作者：
Madison, J. M.;Zhou, F.;Nigam, A.;Hussain, A.;Barker, D. D.;Nehme, R.;van der Ven, K.;Hsu, J.;Wolf, P.;Fleishman, M.;O'Dushlaine, C.;Rose, S.;Chambert, K.;Lau, F. H.;Ahfeldt, T.;Rueckert, E. H.;Sheridan, S. D.;Fass, D. M.;Nemesh, J.;Mullen, T. E.;Daheron, L.;McCarroll, S.;Sklar, P.;Perlis, R. H.;Haggarty, S. J.
双相情感障碍（BD）是一种常见的神经精神疾病，其特征是慢性反复发作的抑郁和躁狂。尽管有证据表明BD具有高遗传性，但对其潜在的病理生理学知之甚少。为了开发新的工具来研究BD的分子和细胞基础，我们应用了一种基于家族的范式来推导和表征一组12个诱导多能干细胞（iPSC）系，这些细胞系来自由两个BD受影响的兄弟和他们的两个未受影响的父母组成的四重奏。最初，在来自不同家族成员的iPSC之间没有观察到显著的表型差异。然而，在定向神经分化后，我们观察到，与其未受影响的父母相比，来自两名BD患者的表达CXCR 4（CXC趋化因子受体-4）的中枢神经系统（CNS）神经祖细胞（NPC）在神经发生和对神经可塑性至关重要的基因表达水平（包括WNT通路组分和离子通道亚基）上表现出多种表型差异。发现用糖原合成酶激酶3（GSK 3）（一种已知的WNT信号传导调节剂）的药理学抑制剂治疗CXCR 4 + NPC可挽救BD患者NPC中的祖细胞增殖缺陷。总之，这些研究提供了新的细胞工具，解剖BD的病理生理学和参与神经发育和神经可塑性的关键途径失调的证据。未来一代的额外的iPSC，以家族为基础的范例，用于建模复杂的神经精神疾病，结合深入的表型分析，有望提供对BD病理生理学底物的见解，并可能为治疗和理想的预防提供靶向治疗的发展。
Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared to their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4+ NPCs with a pharmacological inhibitor of glycogen synthase kinase 3 (GSK3), a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD-patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention.
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影响因子：
3.7
作者：
Kerner, Berit;Lambert, Christophe G.;Muthen, Bengt O.
通讯作者：
Muthen, Bengt O.
影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
16.2
作者：
Malhotra D;McCarthy S;Michaelson JJ;Vacic V;Burdick KE;Yoon S;Cichon S;Corvin A;Gary S;Gershon ES;Gill M;Karayiorgou M;Kelsoe JR;Krastoshevsky O;Krause V;Leibenluft E;Levy DL;Makarov V;Bhandari A;Malhotra AK;McMahon FJ;Nöthen MM;Potash JB;Rietschel M;Schulze TG;Sebat J
通讯作者：
Sebat J
精神分裂症，躁郁症和抑郁症的跨disor阶层基因组分析。
DOI：
10.1176/appi.ajp.2010.09091335
发表时间：
2010-10
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Huang J;Perlis RH;Lee PH;Rush AJ;Fava M;Sachs GS;Lieberman J;Hamilton SP;Sullivan P;Sklar P;Purcell S;Smoller JW
通讯作者：
Smoller JW
影响因子：
11
作者：
Brennand, K. J.;Simone, A.;Tran, N.;Gage, F. H.
通讯作者：
Gage, F. H.