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; Gabriel Siebiger; Yimu Zhao; Aaron J Clasky; Avinash N Mukkala; Erika L Beroncal; Lauren Banh; Lili Aslostovar; Sonya Brijbassi; Sarah E Hogan; James D McCully; Mohadeseh Mehrabian; Thomas H Petersen; Lisa A Robinson; Melanie Walker; Constantine Zachos; MITO2i-MbD Mitochondrial Transplant Consortium; Sowmya Viswanathan; Frank X Gu; Ori D Rotstein; Marcelo Cypel; Milica Radisic; Ana C Andreazza

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

Stem Cell Res Ther. 2024 May 31;15(1):157. doi: 10.1186/s13287-024-03771-8.

Authors

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. [email protected].
²³ Mitochondrial Innovation Initiative (MITO2i), Toronto, Canada. [email protected].
²⁴ Department of Psychiatry, University of Toronto, Toronto, ON, Canada. [email protected].

^# Contributed equally.

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.

Publication types

Review

MeSH terms

Acute Disease
Animals
Humans
Mitochondria* / metabolism
Mitochondrial Replacement Therapy / methods
Translational Research, Biomedical / methods