c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration

Iolanda Aquila; Eleonora Cianflone; Mariangela Scalise; Fabiola Marino; Teresa Mancuso; Andrea Filardo; Andrew J. Smith; Donato Cappetta; Antonella De Angelis; Konrad Urbanek; Andrea M. Isidori; Michele Torella; Valter Agosti; Giuseppe Viglietto; Bernardo Nadal-Ginard; Georgina M. Ellison-Hughes; Daniele Torella

doi:10.1038/s41419-019-1655-5

c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration

Iolanda Aquila, Eleonora Cianflone, Mariangela Scalise, Fabiola Marino, Teresa Mancuso, Andrea Filardo, Andrew J. Smith, Donato Cappetta, Antonella De Angelis, Konrad Urbanek, Andrea M. Isidori, Michele Torella, Valter Agosti, Giuseppe Viglietto, Bernardo Nadal-Ginard^*, Georgina M. Ellison-Hughes, Daniele Torella

^*Corresponding author for this work

Centre for Human & Applied Physiological Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kit^pos stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kit^Cre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kit^CreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kit^CreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kit^CreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kit^CreKIs severely affects CSCs myogenic potential. c-kit^CreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kit^CreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kit^CreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.

Original language	English
Article number	436
Number of pages	19
Journal	Cell Death and Disease
Volume	10
Early online date	4 Jun 2019
DOIs	https://doi.org/10.1038/s41419-019-1655-5
Publication status	Published - 2019

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c-kit Haploinsufficiency impairs_AQUILA_Accepted30April2019_GOLD VoRFinal published version, 6.2 MBLicence: CC BY

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Aquila, I., Cianflone, E., Scalise, M., Marino, F., Mancuso, T., Filardo, A., Smith, A. J., Cappetta, D., De Angelis, A., Urbanek, K., Isidori, A. M., Torella, M., Agosti, V., Viglietto, G., Nadal-Ginard, B., Ellison-Hughes, G. M., & Torella, D. (2019). c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration. Cell Death and Disease, 10, Article 436. https://doi.org/10.1038/s41419-019-1655-5

@article{8401947368b94f0c9e2c0e8c8f79ecd3,

title = "c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration",

abstract = "An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kitpos stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kitCre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kitCreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kitCreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kitCreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kitCreKIs severely affects CSCs myogenic potential. c-kitCreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kitCreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kitCreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.",

author = "Iolanda Aquila and Eleonora Cianflone and Mariangela Scalise and Fabiola Marino and Teresa Mancuso and Andrea Filardo and Smith, {Andrew J.} and Donato Cappetta and {De Angelis}, Antonella and Konrad Urbanek and Isidori, {Andrea M.} and Michele Torella and Valter Agosti and Giuseppe Viglietto and Bernardo Nadal-Ginard and Ellison-Hughes, {Georgina M.} and Daniele Torella",

year = "2019",

doi = "10.1038/s41419-019-1655-5",

language = "English",

volume = "10",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

}

Aquila, I, Cianflone, E, Scalise, M, Marino, F, Mancuso, T, Filardo, A, Smith, AJ, Cappetta, D, De Angelis, A, Urbanek, K, Isidori, AM, Torella, M, Agosti, V, Viglietto, G, Nadal-Ginard, B, Ellison-Hughes, GM & Torella, D 2019, 'c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration', Cell Death and Disease, vol. 10, 436. https://doi.org/10.1038/s41419-019-1655-5

TY - JOUR

T1 - c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration

AU - Aquila, Iolanda

AU - Cianflone, Eleonora

AU - Scalise, Mariangela

AU - Marino, Fabiola

AU - Mancuso, Teresa

AU - Filardo, Andrea

AU - Smith, Andrew J.

AU - Cappetta, Donato

AU - De Angelis, Antonella

AU - Urbanek, Konrad

AU - Isidori, Andrea M.

AU - Torella, Michele

AU - Agosti, Valter

AU - Viglietto, Giuseppe

AU - Nadal-Ginard, Bernardo

AU - Ellison-Hughes, Georgina M.

AU - Torella, Daniele

PY - 2019

Y1 - 2019

N2 - An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kitpos stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kitCre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kitCreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kitCreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kitCreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kitCreKIs severely affects CSCs myogenic potential. c-kitCreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kitCreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kitCreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.

AB - An overdose of Isoproterenol (ISO) causes acute cardiomyocyte (CM) dropout and activates the resident cardiac c-kitpos stem/progenitor cells (CSCs) generating a burst of new CM formation that replaces those lost to ISO. Recently, unsuccessful attempts to reproduce these findings using c-kitCre knock-in (KI) mouse models were reported. We tested whether c-kit haploinsufficiency in c-kitCreKI mice was the cause of the discrepant results in response to ISO. Male C57BL/6J wild-type (wt) mice and c-kitCreKI mice were given a single dose of ISO (200 and/or 400 mg/Kg s.c.). CM formation was measured with different doses and duration of BrdU or EdU. We compared the myogenic and regenerative potential of the c-kitCreCSCs with wtCSCs. Acute ISO overdose causes LV dysfunction with dose-dependent CM death by necrosis and apoptosis, whose intensity follows a basal-apical and epicardium to sub-endocardium gradient, with the most severe damage confined to the apical sub-endocardium. The damage triggers significant new CM formation mainly in the apical sub-endocardial layer. c-kit haploinsufficiency caused by c-kitCreKIs severely affects CSCs myogenic potential. c-kitCreKI mice post-ISO fail to respond with CSC activation and show reduced CM formation and suffer chronic cardiac dysfunction. Transplantation of wtCSCs rescued the defective regenerative cardiac phenotype of c-kitCreKI mice. Furthermore, BAC-mediated transgenesis of a single c-kit gene copy normalized the functional diploid c-kit content of c-kitCreKI CSCs and fully restored their regenerative competence. Overall, these data show that c-kit haploinsufficiency impairs the endogenous cardioregenerative response after injury affecting CSC activation and CM replacement. Repopulation of c-kit haploinsufficient myocardial tissue with wtCSCs as well c-kit gene deficit correction of haploinsufficient CSCs restores CM replacement and functional cardiac repair. Thus, adult neo-cardiomyogenesis depends on and requires a diploid level of c-kit.

UR - http://www.scopus.com/inward/record.url?scp=85066607270&partnerID=8YFLogxK

U2 - 10.1038/s41419-019-1655-5

DO - 10.1038/s41419-019-1655-5

M3 - Article

AN - SCOPUS:85066607270

SN - 2041-4889

VL - 10

JO - Cell Death and Disease

JF - Cell Death and Disease

M1 - 436

ER -

c-kit Haploinsufficiency impairs adult cardiac stem cell growth, myogenicity and myocardial regeneration

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