Tomatidine-stimulated maturation of human embryonic stem cell-derived cardiomyocytes for modeling mitochondrial dysfunction.
Journal
Experimental & molecular medicine
ISSN: 2092-6413
Titre abrégé: Exp Mol Med
Pays: United States
ID NLM: 9607880
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
28
04
2021
accepted:
19
10
2021
revised:
22
08
2021
pubmed:
6
4
2022
medline:
11
5
2022
entrez:
5
4
2022
Statut:
ppublish
Résumé
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have been reported to exhibit immature embryonic or fetal cardiomyocyte-like phenotypes. To enhance the maturation of hESC-CMs, we identified a natural steroidal alkaloid, tomatidine, as a new substance that stimulates the maturation of hESC-CMs. Treatment of human embryonic stem cells with tomatidine during cardiomyocyte differentiation stimulated the expression of several cardiomyocyte-specific markers and increased the density of T-tubules. Furthermore, tomatidine treatment augmented the number and size of mitochondria and enhanced the formation of mitochondrial lamellar cristae. Tomatidine treatment stimulated mitochondrial functions, including mitochondrial membrane potential, oxidative phosphorylation, and ATP production, in hESC-CMs. Tomatidine-treated hESC-CMs were more sensitive to doxorubicin-induced cardiotoxicity than the control cells. In conclusion, the present study suggests that tomatidine promotes the differentiation of stem cells to adult cardiomyocytes by accelerating mitochondrial biogenesis and maturation and that tomatidine-treated mature hESC-CMs can be used for cardiotoxicity screening and cardiac disease modeling.
Identifiants
pubmed: 35379934
doi: 10.1038/s12276-022-00746-8
pii: 10.1038/s12276-022-00746-8
pmc: PMC9076832
doi:
Substances chimiques
tomatidine
2B73S48786
Tomatine
31U6547O08
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
493-502Informations de copyright
© 2022. The Author(s).
Références
Ferri, N. et al. Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. Pharmacol. Ther. 138, 470–484 (2013).
pubmed: 23507039
doi: 10.1016/j.pharmthera.2013.03.005
Gintant, G., Sager, P. T. & Stockbridge, N. Evolution of strategies to improve preclinical cardiac safety testing. Nat. Rev. Drug Discov. 15, 457–471 (2016).
pubmed: 26893184
doi: 10.1038/nrd.2015.34
Stella Stoter, A. M., Hirt, M. N., Stenzig, J. & Weinberger, F. Assessment of cardiotoxicity with stem cell-based strategies. Clin. Ther. 42, 1892–1910 (2020).
pubmed: 32938533
doi: 10.1016/j.clinthera.2020.08.012
Lian, X. et al. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions. Nat. Protoc. 8, 162–175 (2013).
pubmed: 23257984
doi: 10.1038/nprot.2012.150
Zhu, W. Z., Santana, L. F. & Laflamme, M. A. Local control of excitation-contraction coupling in human embryonic stem cell-derived cardiomyocytes. PLoS ONE 4, e5407 (2009).
pubmed: 19404384
pmcid: 2671137
doi: 10.1371/journal.pone.0005407
Karbassi, E. et al. Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine. Nat. Rev. Cardiol. 17, 341–359 (2020).
pubmed: 32015528
pmcid: 7239749
doi: 10.1038/s41569-019-0331-x
Robertson, C., Tran, D. D. & George, S. C. Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells 31, 829–837 (2013).
pubmed: 23355363
doi: 10.1002/stem.1331
Varga, Z. V., Ferdinandy, P., Liaudet, L. & Pacher, P. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am. J. Physiol. Heart Circ. Physiol. 309, H1453–H1467 (2015).
pubmed: 26386112
pmcid: 4666974
doi: 10.1152/ajpheart.00554.2015
Ikon, N. & Ryan, R. O. Cardiolipin and mitochondrial cristae organization. Biochim. Biophys. Acta Biomembr. 1859, 1156–1163 (2017).
pubmed: 28336315
doi: 10.1016/j.bbamem.2017.03.013
Goormaghtigh, E., Huart, P., Praet, M., Brasseur, R. & Ruysschaert, J. M. Structure of the adriamycin-cardiolipin complex. Role in mitochondrial toxicity. Biophys. Chem. 35, 247–257 (1990).
pubmed: 2204444
doi: 10.1016/0301-4622(90)80012-V
Aryal, B. & Rao, V. A. Deficiency in cardiolipin reduces doxorubicin-induced oxidative stress and mitochondrial damage in human B-lymphocytes. PLoS ONE 11, e0158376 (2016).
pubmed: 27434059
pmcid: 4951097
doi: 10.1371/journal.pone.0158376
Wallace, K. B., Sardao, V. A. & Oliveira, P. J. Mitochondrial determinants of doxorubicin-induced cardiomyopathy. Circ. Res. 126, 926–941 (2020).
pubmed: 32213135
pmcid: 7121924
doi: 10.1161/CIRCRESAHA.119.314681
Cui, N. et al. Doxorubicin-induced cardiotoxicity is maturation dependent due to the shift from topoisomerase IIalpha to IIbeta in human stem cell derived cardiomyocytes. J. Cell Mol. Med. 23, 4627–4639 (2019).
pubmed: 31106979
pmcid: 6584544
doi: 10.1111/jcmm.14346
Waltz, T. B. et al. Sarcopenia, aging and prospective interventional strategies. Curr. Med. Chem. 25, 5588–5596 (2018).
pubmed: 28762310
pmcid: 5792375
doi: 10.2174/0929867324666170801095850
Jiang, Q. W. et al. Therapeutic potential of steroidal alkaloids in cancer and other diseases. Med. Res. Rev. 36, 119–143 (2016).
pubmed: 25820039
doi: 10.1002/med.21346
Dyle, M. C. et al. Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. J. Biol. Chem. 289, 14913–14924 (2014).
pubmed: 24719321
pmcid: 4031541
doi: 10.1074/jbc.M114.556241
Ebert, S. M. et al. Identification and small molecule inhibition of an activating transcription factor 4 (ATF4)-dependent pathway to age-related skeletal muscle weakness and atrophy. J. Biol. Chem. 290, 25497–25511 (2015).
pubmed: 26338703
pmcid: 4646196
doi: 10.1074/jbc.M115.681445
Rutkowski, D. T. & Kaufman, R. J. All roads lead to ATF4. Dev. Cell 4, 442–444 (2003).
pubmed: 12689582
doi: 10.1016/S1534-5807(03)00100-X
Fang, E. F. et al. Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci. Rep. 7, 46208 (2017).
pubmed: 28397803
pmcid: 5387417
doi: 10.1038/srep46208
Yang, X., Pabon, L. & Murry, C. E. Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ. Res. 114, 511–523 (2014).
pubmed: 24481842
pmcid: 3955370
doi: 10.1161/CIRCRESAHA.114.300558
Brette, F. & Orchard, C. T-tubule function in mammalian cardiac myocytes. Circ. Res. 92, 1182–1192 (2003).
pubmed: 12805236
doi: 10.1161/01.RES.0000074908.17214.FD
De La Mata, A. et al. BIN1 induces the formation of T-tubules and adult-like Ca(2+) release units in developing cardiomyocytes. Stem Cells 37, 54–64 (2019).
doi: 10.1002/stem.2927
Hong, T. et al. Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat. Med. 20, 624–632 (2014).
pubmed: 24836577
pmcid: 4048325
doi: 10.1038/nm.3543
Takeshima, H., Komazaki, S., Nishi, M., Iino, M. & Kangawa, K. Junctophilins: a novel family of junctional membrane complex proteins. Mol. Cell 6, 11–22 (2000).
pubmed: 10949023
Folmes, C. D., Dzeja, P. P., Nelson, T. J. & Terzic, A. Mitochondria in control of cell fate. Circ. Res. 110, 526–529 (2012).
pubmed: 22343555
pmcid: 3491643
doi: 10.1161/RES.0b013e31824ae5c1
Chung, S. et al. Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat. Clin. Pract. Cardiovasc. Med. 4, S60–S67 (2007).
pubmed: 17230217
pmcid: 3232050
doi: 10.1038/ncpcardio0766
Katz, A. M. & Lorell, B. H. Regulation of cardiac contraction and relaxation. Circulation 102, IV69–IV74 (2000).
pubmed: 11080134
doi: 10.1161/circ.102.suppl_4.IV-69
Li, G. R. & Dong, M. Q. Pharmacology of cardiac potassium channels. Adv. Pharmacol. 59, 93–134 (2010).
pubmed: 20933200
doi: 10.1016/S1054-3589(10)59004-5
Aas, T. et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat. Med. 2, 811–814 (1996).
pubmed: 8673929
doi: 10.1038/nm0796-811
Kuerer, H. M. et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J. Clin. Oncol. 17, 460–469 (1999).
pubmed: 10080586
doi: 10.1200/JCO.1999.17.2.460
Singal, P. K. & Iliskovic, N. Doxorubicin-induced cardiomyopathy. N. Engl. J. Med. 339, 900–905 (1998).
pubmed: 9744975
doi: 10.1056/NEJM199809243391307
Von Hoff, D. D. et al. Risk factors for doxorubicin-induced congestive heart failure. Ann. Intern. Med. 91, 710–717 (1979).
doi: 10.7326/0003-4819-91-5-710
Zhang, S. et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 18, 1639–1642 (2012).
pubmed: 23104132
doi: 10.1038/nm.2919
Chatterjee, K., Zhang, J., Honbo, N. & Karliner, J. S. Doxorubicin cardiomyopathy. Cardiology 115, 155–162 (2010).
pubmed: 20016174
doi: 10.1159/000265166
Tamai, T. et al. Rheb (Ras homologue enriched in brain)-dependent mammalian target of rapamycin complex 1 (mTORC1) activation becomes indispensable for cardiac hypertrophic growth after early postnatal period. J. Biol. Chem. 288, 10176–10187 (2013).
pubmed: 23426372
pmcid: 3617260
doi: 10.1074/jbc.M112.423640
Kunkel, S. D. et al. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab. 13, 627–638 (2011).
pubmed: 21641545
pmcid: 3120768
doi: 10.1016/j.cmet.2011.03.020
Chen, J. et al. Ursolic acid induces mitochondrial biogenesis through the activation of AMPK and PGC-1 in C2C12 myotubes: a possible mechanism underlying its beneficial effect on exercise endurance. Food Funct. 8, 2425–2436 (2017).
pubmed: 28675237
doi: 10.1039/C7FO00127D
Hasan, A. et al. Age-dependent maturation of iPSC-CMs leads to the enhanced compartmentation of beta2AR-cAMP signalling. Cells 9, 2275 (2020).
pmcid: 7601768
doi: 10.3390/cells9102275
Lee, Y. K. et al. Triiodothyronine promotes cardiac differentiation and maturation of embryonic stem cells via the classical genomic pathway. Mol. Endocrinol. 24, 1728–1736 (2010).
pubmed: 20667986
pmcid: 5417405
doi: 10.1210/me.2010-0032
Kuppusamy, K. T. et al. Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes. Proc. Natl Acad. Sci. USA 112, E2785–E2794 (2015).
pubmed: 25964336
pmcid: 4450404
doi: 10.1073/pnas.1424042112
Montessuit, C., Palma, T., Viglino, C., Pellieux, C. & Lerch, R. Effects of insulin-like growth factor-I on the maturation of metabolism in neonatal rat cardiomyocytes. Pflug. Arch. 452, 380–386 (2006).
doi: 10.1007/s00424-006-0059-4
Kim, C. et al. Non-cardiomyocytes influence the electrophysiological maturation of human embryonic stem cell-derived cardiomyocytes during differentiation. Stem Cells Dev. 19, 783–795 (2010).
pubmed: 20001453
doi: 10.1089/scd.2009.0349
Yoshida, S. et al. Maturation of human induced pluripotent stem cell-derived cardiomyocytes by soluble factors from human mesenchymal stem cells. Mol. Ther. 26, 2681–2695 (2018).
pubmed: 30217728
pmcid: 6224789
doi: 10.1016/j.ymthe.2018.08.012
Yang, X. et al. Fatty acids enhance the maturation of cardiomyocytes derived from human pluripotent stem cells. Stem Cell Rep. 13, 657–668 (2019).
doi: 10.1016/j.stemcr.2019.08.013
Snir, M. et al. Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 285, H2355–H2363 (2003).
pubmed: 14613910
doi: 10.1152/ajpheart.00020.2003
Huang, C. Y. et al. Enhancement of human iPSC-derived cardiomyocyte maturation by chemical conditioning in a 3D environment. J. Mol. Cell Cardiol. 138, 1–11 (2020).
pubmed: 31655038
doi: 10.1016/j.yjmcc.2019.10.001
Ronaldson-Bouchard, K. et al. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556, 239–243 (2018).
pubmed: 29618819
pmcid: 5895513
doi: 10.1038/s41586-018-0016-3
Liu, A. et al. Functional characterization of inward rectifier potassium ion channel in murine fetal ventricular cardiomyocytes. Cell Physiol. Biochem. 26, 413–420 (2010).
pubmed: 20798526
doi: 10.1159/000320565
Dhamoon, A. S. & Jalife, J. The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm 2, 316–324 (2005).
pubmed: 15851327
doi: 10.1016/j.hrthm.2004.11.012
Ge, F., Wang, Z. & Xi, J. J. Engineered maturation approaches of human pluripotent stem cell-derived ventricular cardiomyocytes. Cells 9, 9 (2019).
pmcid: 7016801
doi: 10.3390/cells9010009
Feric, N. T. & Radisic, M. Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues. Adv. Drug Deliv. Rev. 96, 110–134 (2016).
pubmed: 25956564
doi: 10.1016/j.addr.2015.04.019
Lesmana, R. et al. Thyroid hormone stimulation of autophagy is essential for mitochondrial biogenesis and activity in skeletal muscle. Endocrinology 157, 23–38 (2016).
pubmed: 26562261
doi: 10.1210/en.2015-1632
Dorn, G. W. 2nd, Vega, R. B. & Kelly, D. P. Mitochondrial biogenesis and dynamics in the developing and diseased heart. Genes Dev. 29, 1981–1991 (2015).
pubmed: 26443844
pmcid: 4604339
doi: 10.1101/gad.269894.115
Cui, A. et al. Dexamethasone-induced Kruppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia. J. Clin. Invest. 129, 2266–2278 (2019).
pubmed: 31033478
pmcid: 6546458
doi: 10.1172/JCI66062
Bocco, B. M. et al. Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression in skeletal muscle. J. Physiol. 594, 5255–5269 (2016).
pubmed: 27302464
pmcid: 5023700
doi: 10.1113/JP272440
Schuler, M. et al. PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab. 4, 407–414 (2006).
pubmed: 17084713
doi: 10.1016/j.cmet.2006.10.003
Maillet, A. et al. Modeling doxorubicin-induced cardiotoxicity in human pluripotent stem cell derived-cardiomyocytes. Sci. Rep. 6, 25333 (2016).
pubmed: 27142468
pmcid: 4855185
doi: 10.1038/srep25333