A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation.
A Study of Gene Expression, Structure, and Contractility of iPSC-Derived Cardiac Myocytes from a Family with Heart Disease due to LMNA Mutation.
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DOI：
10.1007/s10439-021-02850-8
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发表时间：
2021-12
影响因子：
3.8
通讯作者：
Grosberg A
中科院分区：
文献类型：
--
作者：
Mehrabi M;Morris TA;Cang Z;Nguyen CHH;Sha Y;Asad MN;Khachikyan N;Greene TL;Becker DM;Nie Q;Zaragoza MV;Grosberg A
Lamin A/C基因（LMNA）的基因突变可导致心脏病，但使心脏组织特别容易受到突变影响的机制在很大程度上仍然未知。此外，患有LMNA突变的患者在心脏病进展和类型方面具有高度可变的表现。体外患者特异性实验可以为研究这一现象提供一个强大的平台，但使用诱导多能干细胞衍生的心肌细胞（iPSC-CM）会引入成熟度和功能的异质性，从而使任何单一实验结果的解释复杂化。我们假设，将单细胞RNA测序（scRNA-seq）与组织结构和收缩功能的分析结合起来，将阐明一些可能的机制。为了验证这一点，我们研究了5个iPSC-CM系、3个对照组和2个携带（c.357-2A>G）突变的患者。与对照iPSC-CM组织相比，患者iPSC-CM组织的应激产生潜力明显减弱，证明了我们的体外方法的可行性。通过scRNA-seq鉴定对照系和患者系之间的差异表达基因。其中一些与定量结构和功能变化相关的基因是心脏特异性的，这解释了在患者中看到的疾病进展的靶向性。这项工作的结果证明了结合体外工具在探索心脏病机制方面的效用。在线版本包含补充材料，可在10.1007/s10439-021-02850-8获得。
Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics. The online version contains supplementary material available at 10.1007/s10439-021-02850-8.
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影响因子：
6.1
作者：
Grosberg A;Alford PW;McCain ML;Parker KK
通讯作者：
Parker KK
DOI：
10.1016/j.vascn.2012.04.001
发表时间：
2012-05
影响因子：
1.9
作者：
Grosberg A;Nesmith AP;Goss JA;Brigham MD;McCain ML;Parker KK
通讯作者：
Parker KK
影响因子：
14
作者：
Feinberg, Adam W.;Alford, Patrick W.;Jin, Hongwei;Ripplinger, Crystal M.;Werdich, Andreas A.;Sheehy, Sean P.;Grosberg, Anna;Parker, Kevin Kit
通讯作者：
Parker, Kevin Kit
DOI：
10.1109/34.709565
发表时间：
1998-08-01
影响因子：
23.6
作者：
Hong, L;Wan, YF;Jain, A
通讯作者：
Jain, A
影响因子：
3.7
作者：
Araújo T;Aresta G;Castro E;Rouco J;Aguiar P;Eloy C;Polónia A;Campilho A
通讯作者：
Campilho A