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Article

Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip

by
Martta Häkli
1,†,
Satu Jäntti
2,†,
Tiina Joki
2,
Lassi Sukki
3,
Kaisa Tornberg
3,
Katriina Aalto-Setälä
1,4,
Pasi Kallio
3,
Mari Pekkanen-Mattila
1 and
Susanna Narkilahti
2,*
1
Heart Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland
2
Neuro Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland
3
Micro- and Nanosystems Research Group, Faculty of Medicine and Health Technology, Tampere University, 33720 Tampere, Finland
4
Heart Hospital, Tampere University Hospital, 33520 Tampere, Finland
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(6), 3148; https://doi.org/10.3390/ijms23063148
Submission received: 7 February 2022 / Revised: 11 March 2022 / Accepted: 11 March 2022 / Published: 15 March 2022
(This article belongs to the Special Issue Advanced Models of Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Organ-on-a-Chips)
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Abstract

The cardiac autonomic nervous system (cANS) regulates cardiac function by innervating cardiac tissue with axons, and cardiomyocytes (CMs) and neurons undergo comaturation during the heart innervation in embryogenesis. As cANS is essential for cardiac function, its dysfunctions might be fatal; therefore, cardiac innervation models for studying embryogenesis, cardiac diseases, and drug screening are needed. However, previously reported neuron-cardiomyocyte (CM) coculture chips lack studies of functional neuron–CM interactions with completely human-based cell models. Here, we present a novel completely human cell-based and electrophysiologically functional cardiac innervation on a chip in which a compartmentalized microfluidic device, a 3D3C chip, was used to coculture human induced pluripotent stem cell (hiPSC)-derived neurons and CMs. The 3D3C chip enabled the coculture of both cell types with their respective culture media in their own compartments while allowing the neuronal axons to traverse between the compartments via microtunnels connecting the compartments. Furthermore, the 3D3C chip allowed the use of diverse analysis methods, including immunocytochemistry, RT-qPCR and video microscopy. This system resembled the in vivo axon-mediated neuron–CM interaction. In this study, the evaluation of the CM beating response during chemical stimulation of neurons showed that hiPSC-neurons and hiPSC-CMs formed electrophysiologically functional axon-mediated interactions.
Keywords: neuron; cardiomyocyte; coculture; axon-mediated; functional interaction; human-induced pluripotent stem cell; organ-on-chip; microfluidic chip neuron; cardiomyocyte; coculture; axon-mediated; functional interaction; human-induced pluripotent stem cell; organ-on-chip; microfluidic chip
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MDPI and ACS Style

Häkli, M.; Jäntti, S.; Joki, T.; Sukki, L.; Tornberg, K.; Aalto-Setälä, K.; Kallio, P.; Pekkanen-Mattila, M.; Narkilahti, S. Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip. Int. J. Mol. Sci. 2022, 23, 3148. https://doi.org/10.3390/ijms23063148

AMA Style

Häkli M, Jäntti S, Joki T, Sukki L, Tornberg K, Aalto-Setälä K, Kallio P, Pekkanen-Mattila M, Narkilahti S. Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip. International Journal of Molecular Sciences. 2022; 23(6):3148. https://doi.org/10.3390/ijms23063148

Chicago/Turabian Style

Häkli, Martta, Satu Jäntti, Tiina Joki, Lassi Sukki, Kaisa Tornberg, Katriina Aalto-Setälä, Pasi Kallio, Mari Pekkanen-Mattila, and Susanna Narkilahti. 2022. "Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip" International Journal of Molecular Sciences 23, no. 6: 3148. https://doi.org/10.3390/ijms23063148

APA Style

Häkli, M., Jäntti, S., Joki, T., Sukki, L., Tornberg, K., Aalto-Setälä, K., Kallio, P., Pekkanen-Mattila, M., & Narkilahti, S. (2022). Human Neurons Form Axon-Mediated Functional Connections with Human Cardiomyocytes in Compartmentalized Microfluidic Chip. International Journal of Molecular Sciences, 23(6), 3148. https://doi.org/10.3390/ijms23063148

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