Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

Christine M. Poch; Kylie S. Foo; Maria Teresa De Angelis; Karin Jennbacken; Gianluca Santamaria; Andrea Bähr; Qing Dong Wang; Franziska Reiter; Nadja Hornaschewitz; Dorota Zawada; Tarik Bozoglu; Ilaria My; Anna Meier; Tatjana Dorn; Simon Hege; Miia L. Lehtinen; Yat Long Tsoi; Daniel Hovdal; Johan Hyllner; Sascha Schwarz; Stefanie Sudhop; Victoria Jurisch; Marcella Sini; Mick D. Fellows; Matthew Cummings; Jonathan Clarke; Ricardo Baptista; Elif Eroglu; Eckhard Wolf; Nikolai Klymiuk; Kun Lu; Roland Tomasi; Andreas Dendorfer; Marco Gaspari; Elvira Parrotta; Giovanni Cuda; Markus Krane; Daniel Sinnecker; Petra Hoppmann; Christian Kupatt; Regina Fritsche-Danielson; Alessandra Moretti; Kenneth R. Chien; Karl Ludwig Laugwitz

doi:10.1038/s41556-022-00899-8

Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

Christine M. Poch, Kylie S. Foo, Maria Teresa De Angelis, Karin Jennbacken, Gianluca Santamaria, Andrea Bähr, Qing Dong Wang, Franziska Reiter, Nadja Hornaschewitz, Dorota Zawada, Tarik Bozoglu, Ilaria My, Anna Meier, Tatjana Dorn, Simon Hege, Miia L. Lehtinen, Yat Long Tsoi, Daniel Hovdal, Johan Hyllner, Sascha SchwarzStefanie Sudhop, Victoria Jurisch, Marcella Sini, Mick D. Fellows, Matthew Cummings, Jonathan Clarke, Ricardo Baptista, Elif Eroglu, Eckhard Wolf, Nikolai Klymiuk, Kun Lu, Roland Tomasi, Andreas Dendorfer, Marco Gaspari, Elvira Parrotta, Giovanni Cuda, Markus Krane, Daniel Sinnecker, Petra Hoppmann, Christian Kupatt, Regina Fritsche-Danielson, Alessandra Moretti, Kenneth R. Chien, Karl Ludwig Laugwitz

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

26 Scopus citations

Abstract

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

Original language	English
Pages (from-to)	659-671
Number of pages	13
Journal	Nature Cell Biology
Volume	24
Issue number	5
DOIs	https://doi.org/10.1038/s41556-022-00899-8
State	Published - May 2022

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Poch, C. M., Foo, K. S., De Angelis, M. T., Jennbacken, K., Santamaria, G., Bähr, A., Wang, Q. D., Reiter, F., Hornaschewitz, N., Zawada, D., Bozoglu, T., My, I., Meier, A., Dorn, T., Hege, S., Lehtinen, M. L., Tsoi, Y. L., Hovdal, D., Hyllner, J., ... Laugwitz, K. L. (2022). Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors. Nature Cell Biology, 24(5), 659-671. https://doi.org/10.1038/s41556-022-00899-8

@article{28c03e11ff2b4dc9a9fc9b5fb8cb8ede,

title = "Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors",

abstract = "Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.",

author = "Poch, {Christine M.} and Foo, {Kylie S.} and {De Angelis}, {Maria Teresa} and Karin Jennbacken and Gianluca Santamaria and Andrea B{\"a}hr and Wang, {Qing Dong} and Franziska Reiter and Nadja Hornaschewitz and Dorota Zawada and Tarik Bozoglu and Ilaria My and Anna Meier and Tatjana Dorn and Simon Hege and Lehtinen, {Miia L.} and Tsoi, {Yat Long} and Daniel Hovdal and Johan Hyllner and Sascha Schwarz and Stefanie Sudhop and Victoria Jurisch and Marcella Sini and Fellows, {Mick D.} and Matthew Cummings and Jonathan Clarke and Ricardo Baptista and Elif Eroglu and Eckhard Wolf and Nikolai Klymiuk and Kun Lu and Roland Tomasi and Andreas Dendorfer and Marco Gaspari and Elvira Parrotta and Giovanni Cuda and Markus Krane and Daniel Sinnecker and Petra Hoppmann and Christian Kupatt and Regina Fritsche-Danielson and Alessandra Moretti and Chien, {Kenneth R.} and Laugwitz, {Karl Ludwig}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = may,

doi = "10.1038/s41556-022-00899-8",

language = "English",

volume = "24",

pages = "659--671",

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Poch, CM, Foo, KS, De Angelis, MT, Jennbacken, K, Santamaria, G, Bähr, A, Wang, QD, Reiter, F, Hornaschewitz, N, Zawada, D, Bozoglu, T, My, I, Meier, A, Dorn, T, Hege, S, Lehtinen, ML, Tsoi, YL, Hovdal, D, Hyllner, J, Schwarz, S, Sudhop, S, Jurisch, V, Sini, M, Fellows, MD, Cummings, M, Clarke, J, Baptista, R, Eroglu, E, Wolf, E, Klymiuk, N, Lu, K, Tomasi, R, Dendorfer, A, Gaspari, M, Parrotta, E, Cuda, G, Krane, M, Sinnecker, D, Hoppmann, P, Kupatt, C, Fritsche-Danielson, R, Moretti, A, Chien, KR & Laugwitz, KL 2022, 'Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors', Nature Cell Biology, vol. 24, no. 5, pp. 659-671. https://doi.org/10.1038/s41556-022-00899-8

TY - JOUR

T1 - Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

AU - Poch, Christine M.

AU - Foo, Kylie S.

AU - De Angelis, Maria Teresa

AU - Jennbacken, Karin

AU - Santamaria, Gianluca

AU - Bähr, Andrea

AU - Wang, Qing Dong

AU - Reiter, Franziska

AU - Hornaschewitz, Nadja

AU - Zawada, Dorota

AU - Bozoglu, Tarik

AU - My, Ilaria

AU - Meier, Anna

AU - Dorn, Tatjana

AU - Hege, Simon

AU - Lehtinen, Miia L.

AU - Tsoi, Yat Long

AU - Hovdal, Daniel

AU - Hyllner, Johan

AU - Schwarz, Sascha

AU - Sudhop, Stefanie

AU - Jurisch, Victoria

AU - Sini, Marcella

AU - Fellows, Mick D.

AU - Cummings, Matthew

AU - Clarke, Jonathan

AU - Baptista, Ricardo

AU - Eroglu, Elif

AU - Wolf, Eckhard

AU - Klymiuk, Nikolai

AU - Lu, Kun

AU - Tomasi, Roland

AU - Dendorfer, Andreas

AU - Gaspari, Marco

AU - Parrotta, Elvira

AU - Cuda, Giovanni

AU - Krane, Markus

AU - Sinnecker, Daniel

AU - Hoppmann, Petra

AU - Kupatt, Christian

AU - Fritsche-Danielson, Regina

AU - Moretti, Alessandra

AU - Chien, Kenneth R.

AU - Laugwitz, Karl Ludwig

PY - 2022/5

Y1 - 2022/5

N2 - Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

AB - Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host–graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

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U2 - 10.1038/s41556-022-00899-8

DO - 10.1038/s41556-022-00899-8

M3 - Article

C2 - 35550611

AN - SCOPUS:85129824567

SN - 1465-7392

VL - 24

SP - 659

EP - 671

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 5

ER -

Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

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