In silico Cell Therapy Model Restores Failing Human Myocyte Electrophysiology and Calcium Cycling in Fibrotic Myocardium.
In silico Cell Therapy Model Restores Failing Human Myocyte Electrophysiology and Calcium Cycling in Fibrotic Myocardium.
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DOI：
10.3389/fphys.2021.755881
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发表时间：
2021
影响因子：
4
通讯作者：
Mayourian J
中科院分区：
文献类型：
--
作者：
Phillips KG;Turnbull IC;Hajjar RJ;Costa KD;Mayourian J
人c-kit+心脏间质细胞（hCIC）和人间充质干细胞（hMSC）的心肌递送，一种用于治疗衰竭心脏的新兴方法，由于对宿主心肌的影响的不完全理解而受到限制。这项计算研究的目的是模拟hCIC和hMSC对健康和患病的人类心肌细胞（hCM）的电生理学和钙循环的影响，并揭示了一种可能的心脏益处，独立于假定的再生过程。首先，我们开发了一个原始的hCIC的数学模型与不同的实验确定的离子电流组成的电气配置文件。接下来，我们通过确认该模型代表已发表的hCIC全细胞电生理学实验以及hCIC与啮齿动物心肌细胞共培养的实验来验证该模型。然后，我们使用我们的模型来比较hCIC与其他不可兴奋细胞的电生理学效应，以及临床相关的hCIC-hMSC组合疗法和融合的hCIC-hMSC嵌合体。与hMSC相比，通过间隙连接将hCIC直接偶联至健康或衰竭的hCM的模拟导致钙循环的更大增加，动作电位时程（APD）的减少较少。与单独偶联的hCIC或hMSC相比，hCIC和hMSC与健康或患病的hCM的组合偶联导致对电生理学和钙循环的中间效应。与单独或组合的细胞处理相比，融合的hCIC-hMSC嵌合体降低健康和患病的hCM APD和钙瞬变幅度。最后，为了为优化基于细胞的治疗提供理论基础，我们随机化了2,500个模型，这些模型包含可变的hMSC和hCIC干预措施，并模拟了它们对恢复患病心肌细胞电生理和钙处理的影响。置换模拟预测了在纤维化而非非纤维化心肌中纠正心力衰竭hCM的异常性质的能力。该置换实验还预测旁分泌信号传导是这种校正的必要和充分的机制，抵消了纤维化效应，同时还恢复了与糖尿病相关的指标，如上行速度和静息膜电位。总之，我们的计算机模拟研究结果表明，旁分泌信号传导的抗纤维化作用对于消除纤维化心力衰竭中的病理性心肌细胞电生理学和钙循环至关重要，并支持进一步研究提供优化的细胞分泌组作为改善心力衰竭治疗的潜在策略。
Myocardial delivery of human c-kit+ cardiac interstitial cells (hCICs) and human mesenchymal stem cells (hMSCs), an emerging approach for treating the failing heart, has been limited by an incomplete understanding of the effects on host myocardium. This computational study aims to model hCIC and hMSC effects on electrophysiology and calcium cycling of healthy and diseased human cardiomyocytes (hCM), and reveals a possible cardiotherapeutic benefit independent of putative regeneration processes. First, we developed an original hCIC mathematical model with an electrical profile comprised of distinct experimentally identified ion currents. Next, we verified the model by confirming it is representative of published experiments on hCIC whole-cell electrophysiology and on hCIC co-cultures with rodent cardiomyocytes. We then used our model to compare electrophysiological effects of hCICs to other non-excitable cells, as well as clinically relevant hCIC-hMSC combination therapies and fused hCIC-hMSC CardioChimeras. Simulation of direct coupling of hCICs to healthy or failing hCMs through gap junctions led to greater increases in calcium cycling with lesser reductions in action potential duration (APD) compared with hMSCs. Combined coupling of hCICs and hMSCs to healthy or diseased hCMs led to intermediate effects on electrophysiology and calcium cycling compared to individually coupled hCICs or hMSCs. Fused hCIC-hMSC CardioChimeras decreased healthy and diseased hCM APD and calcium transient amplitude compared to individual or combined cell treatments. Finally, to provide a theoretical basis for optimizing cell-based therapies, we randomized populations of 2,500 models incorporating variable hMSC and hCIC interventions and simulated their effects on restoring diseased cardiomyocyte electrophysiology and calcium handling. The permutation simulation predicted the ability to correct abnormal properties of heart failure hCMs in fibrotic, but not non-fibrotic, myocardium. This permutation experiment also predicted paracrine signaling to be a necessary and sufficient mechanism for this correction, counteracting the fibrotic effects while also restoring arrhythmia-related metrics such as upstroke velocity and resting membrane potential. Altogether, our in silico findings suggest anti-fibrotic effects of paracrine signaling are critical to abrogating pathological cardiomyocyte electrophysiology and calcium cycling in fibrotic heart failure, and support further investigation of delivering an optimized cellular secretome as a potential strategy for improving heart failure therapy.
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影响因子：
5.3
作者：
Che H;Xiao GS;Sun HY;Wang Y;Li GR
通讯作者：
Li GR
影响因子：
120.7
作者：
Heldman, Alan W.;DiFede, Darcy L.;Fishman, Joel E.;Zambrano, Juan P.;Trachtenberg, Barry H.;Karantalis, Vasileios;Mushtaq, Muzammil;Williams, Adam R.;Suncion, Viky Y.;McNiece, Ian K.;Ghersin, Eduard;Soto, Victor;Lopera, Gustavo;Miki, Roberto;Willens, Howard;Hendel, Robert;Mitrani, Raul;Pattany, Pradip;Feigenbaum, Gary;Oskouei, Behzad;Byrnes, John;Lowery, Maureen H.;Sierra, Julio;Pujol, Mariesty V.;Delgado, Cindy;Gonzalez, Phillip J.;Rodriguez, Jose E.;Bagno, Luiza Lima;Rouy, Didier;Altman, Peter;Foo, Cheryl Wong Po;da Silva, Jose;Anderson, Erica;Schwarz, Richard;Mendizabal, Adam;Hare, Joshua M.
通讯作者：
Hare, Joshua M.
影响因子：
20.1
作者：
Karantalis V;DiFede DL;Gerstenblith G;Pham S;Symes J;Zambrano JP;Fishman J;Pattany P;McNiece I;Conte J;Schulman S;Wu K;Shah A;Breton E;Davis-Sproul J;Schwarz R;Feigenbaum G;Mushtaq M;Suncion VY;Lardo AC;Borrello I;Mendizabal A;Karas TZ;Byrnes J;Lowery M;Heldman AW;Hare JM
通讯作者：
Hare JM
合成间充质干细胞的制备用于治疗小鼠急性心肌梗死
影响因子：
20.1
作者：
Luo L;Tang J;Nishi K;Yan C;Dinh PU;Cores J;Kudo T;Zhang J;Li TS;Cheng K
通讯作者：
Cheng K
影响因子：
20.1
作者：
Hatzistergos KE;Quevedo H;Oskouei BN;Hu Q;Feigenbaum GS;Margitich IS;Mazhari R;Boyle AJ;Zambrano JP;Rodriguez JE;Dulce R;Pattany PM;Valdes D;Revilla C;Heldman AW;McNiece I;Hare JM
通讯作者：
Hare JM