Review

. 2024 May 31;15(1):157.

doi: 10.1186/s13287-024-03771-8.

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states

David F Bodenstein^#^{1

2}, Gabriel Siebiger^#^{3

4

2}, Yimu Zhao^#^{5

2}, Aaron J Clasky^#^{6

2}, Avinash N Mukkala^#^{3

7

2}, Erika L Beroncal^#^{1

2}, Lauren Banh^#^{5

8

9}, Lili Aslostovar¹⁰, Sonya Brijbassi², Sarah E Hogan¹¹, James D McCully^{12

13}, Mohadeseh Mehrabian¹⁰, Thomas H Petersen¹¹, Lisa A Robinson¹⁴, Melanie Walker¹⁵, Constantine Zachos²; MITO2i-MbD Mitochondrial Transplant Consortium; Sowmya Viswanathan^{5

8

2}, Frank X Gu^{5

6

2

16}, Ori D Rotstein^{2

17

18}, Marcelo Cypel^{4

2

19}, Milica Radisic^{5

6

2

16

20

21}, Ana C Andreazza^{22

23

24}

Affiliations

¹ Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Room 4211, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
² Mitochondrial Innovation Initiative (MITO2i), Toronto, Canada.
³ Institute of Medical Science (IMS), University of Toronto, Toronto, Canada.
⁴ Latner Thoracic Research Laboratories, Toronto General Hospital, Toronto, Canada.
⁵ Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
⁶ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada.
⁷ Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Canada.
⁸ Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, Canada.
⁹ Krembil Research Institute, University Health Network, Toronto, Canada.
¹⁰ Centre for Commercialization of Regenerative Medicine, Toronto, Canada.
¹¹ Regenerative Medicine Department, United Therapeutics Corporation, Silver Spring, USA.
¹² Harvard Medical School, Boston, USA.
¹³ Department of Cardiac Surgery, Boston Children's Hospital, Boston, USA.
¹⁴ Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Canada.
¹⁵ Department of Neurological Surgery, University of Washington, Seattle, USA.
¹⁶ Acceleration Consortium, University of Toronto, Toronto, ON, Canada.
¹⁷ Li Ka Shing Knowledge Institute, Unity Health Toronto, Toronto, Canada.
¹⁸ Department of Surgery, University of Toronto, Toronto, Canada.
¹⁹ Toronto Lung Transplant Program, Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, M5G 2C4, Canada.
²⁰ Toronto General Hospital Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
²¹ Terence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
²² Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Room 4211, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. ana.andreazza@utoronto.ca.
²³ Mitochondrial Innovation Initiative (MITO2i), Toronto, Canada. ana.andreazza@utoronto.ca.
²⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. ana.andreazza@utoronto.ca.

^# Contributed equally.

PMID: 38816774
PMCID: PMC11140916
DOI: 10.1186/s13287-024-03771-8

Review

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states

David F Bodenstein et al. Stem Cell Res Ther. 2024.

. 2024 May 31;15(1):157.

doi: 10.1186/s13287-024-03771-8.

Authors

Affiliations

¹ Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Room 4211, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
² Mitochondrial Innovation Initiative (MITO2i), Toronto, Canada.
³ Institute of Medical Science (IMS), University of Toronto, Toronto, Canada.
⁴ Latner Thoracic Research Laboratories, Toronto General Hospital, Toronto, Canada.
⁵ Institute of Biomedical Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.
⁶ Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada.
⁷ Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Canada.
⁸ Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, Canada.
⁹ Krembil Research Institute, University Health Network, Toronto, Canada.
¹⁰ Centre for Commercialization of Regenerative Medicine, Toronto, Canada.
¹¹ Regenerative Medicine Department, United Therapeutics Corporation, Silver Spring, USA.
¹² Harvard Medical School, Boston, USA.
¹³ Department of Cardiac Surgery, Boston Children's Hospital, Boston, USA.
¹⁴ Program in Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Canada.
¹⁵ Department of Neurological Surgery, University of Washington, Seattle, USA.
¹⁶ Acceleration Consortium, University of Toronto, Toronto, ON, Canada.
¹⁷ Li Ka Shing Knowledge Institute, Unity Health Toronto, Toronto, Canada.
¹⁸ Department of Surgery, University of Toronto, Toronto, Canada.
¹⁹ Toronto Lung Transplant Program, Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, M5G 2C4, Canada.
²⁰ Toronto General Hospital Research Institute, University Health Network, Toronto, ON, M5G 2C4, Canada.
²¹ Terence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
²² Department of Pharmacology and Toxicology, University of Toronto, Medical Science Building, Room 4211, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. ana.andreazza@utoronto.ca.
²³ Mitochondrial Innovation Initiative (MITO2i), Toronto, Canada. ana.andreazza@utoronto.ca.
²⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. ana.andreazza@utoronto.ca.

^# Contributed equally.

PMID: 38816774
PMCID: PMC11140916
DOI: 10.1186/s13287-024-03771-8

Abstract

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

Keywords: Ischemia–reperfusion injury; Joint-on-a-chip; Mitochondria; Mitochondrial transplant; Organ-on-a-chip.

PubMed Disclaimer

Conflict of interest statement

SEH and TPJ are paid employees of United Therapeutics. LA and MM are paid employees of the Centre for Commercialization of Regenerative Medicine. MR and YZ are inventors on a patent describing Biowire II heart-on-a-chip technology that is licensed to Valo Health. They receive royalty payments. ACA is the founder and scientific director for MITO2i. No author has or will receive financial incentive of any kind in relation to the technology described herein.

Figures

**Fig. 1**
Overview of the generation of organ-on-a-chip models from iPSCs and their downstream applications. iPSCs are reprogrammed from patient PBMCs or fibroblasts by transfection with OCT4, SOX2, KLF4, L-myc, and Lin28. Following iPSC stabilization, cells are differentiated to desired cell type and seeded on biomaterials and scaffolds to generate organ-on-a-chip models. Organ-on-a-chip models mimic in vivo tissue by replicating intercellular signalling and microenvironment to generate advanced in vitro disease models. Figure created with BioRender.com

**Fig. 2**
Our mitochondrial transplant CWG research plan to investigate the stabilization of isolated mitochondria and therapeutic efficacy in organ-on-a-chip models. Figure created with BioRender.com

See this image and copyright information in PMC

References

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1. Wiedemann N, Pfanner N. Mitochondrial machineries for protein import and assembly. Annu Rev Biochem. 2017;86:685–714. doi: 10.1146/annurev-biochem-060815-014352. - DOI - PubMed
1. Latorre-Pellicer A, Moreno-Loshuertos R, Lechuga-Vieco AV, Sánchez-Cabo F, Torroja C, Acín-Pérez R, et al. Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing. Nature. 2016;535(7613):561–565. doi: 10.1038/nature18618. - DOI - PubMed
1. Emani SM, Piekarski BL, Harrild D, Del Nido PJ, McCully JD. Autologous mitochondrial transplantation for dysfunction after ischemia–reperfusion injury. J Thorac Cardiovasc Surg. 2017;154(1):286–289. doi: 10.1016/j.jtcvs.2017.02.018. - DOI - PubMed

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Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states

Affiliations

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Miscellaneous