Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells

被引：12

作者：

Dark, Nicola ^{[1
]}

Cosson, Marie-Victoire ^{[1
]}

Tsansizi, Lorenza I. ^{[1
,2
]}

Owen, Thomas J. ^{[2
]}

Ferraro, Elisa ^{[1
]}

Francis, Alice J. ^{[2
]}

Tsai, Selina ^{[1
]}

Bouissou, Camille ^{[1
]}

Weston, Anne ^{[1
]}

Collinson, Lucy ^{[1
]}

Abi-Gerges, Najah ^{[3
]}

Miller, Paul E. ^{[3
]}

MacLeod, Kenneth T. ^{[2
]}

Ehler, Elisabeth ^{[4
]}

Mitter, Richard ^{[1
]}

Harding, Sian E. ^{[2
]}

Smith, James C. ^{[1
]}

Bernardo, Andreia S. ^{[1
,2
]}

机构：

[1] Francis Crick Inst, London, England

[2] Imperial Coll London, NHLI, London, England

[3] AnaBios, San Diego, CA USA

[4] Kings Coll London, London, England

来源：

CELL REPORTS METHODS | 2023年 / 3卷 / 04期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

CARDIAC MYOCYTES; GENE-EXPRESSION; HEART; MATURATION; ATRIAL; MUSCLE; PLATFORM; PROTEIN; CYTOARCHITECTURE; DIFFERENTIATION;

D O I：

10.1016/j.crmeth.2023.100456

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

Decreased left ventricle (LV) function caused by genetic mutations or injury often leads to debilitating and fatal cardiovascular disease. LV cardiomyocytes are, therefore, a potentially valuable therapeutical target. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are neither homogeneous nor functionally mature, which reduces their utility. Here, we exploit cardiac development knowledge to instruct differentia-tion of hPSCs specifically toward LV cardiomyocytes. Correct mesoderm patterning and retinoic acid pathway blocking are essential to generate near-homogenous LV-specific hPSC-CMs (hPSC-LV-CMs). These cells transit via first heart field progenitors and display typical ventricular action potentials. Impor-tantly, hPSC-LV-CMs exhibit increased metabolism, reduced proliferation, and improved cytoarchitecture and functional maturity compared with age-matched cardiomyocytes generated using the standard WNT-ON/WNT-OFF protocol. Similarly, engineered heart tissues made from hPSC-LV-CMs are better organized, produce higher force, and beat more slowly but can be paced to physiological levels. Together, we show that functionally matured hPSC-LV-CMs can be obtained rapidly without exposure to current maturation regimes.

引用

页数：32

共 110 条

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