Delphi-driven consensus definition for mesenchymal stromal cells and clinical reporting guidelines for mesenchymal stromal cell-based therapeutics

Laurent Renesme; Kelly D Cobey; Manoj M Lalu; Tania Bubela; Raghavan Chinnadurai; John De Vos; Rod Dunbar; Dean Fergusson; Daniel Freund; Jacques Galipeau; Edwin Horwitz; Maxime Lê; Michael Matthay; David Moher; Jan Nolta; Graham Parker; Donald G Phinney; Mahendra Rao; John E J Rasko; Patricia R M Rocco; Fabio Rossi; Michael Rosu Myles; Sowmya Viswanathan; Bernard Thébaud

doi:10.1016/j.jcyt.2024.10.008

Delphi-driven consensus definition for mesenchymal stromal cells and clinical reporting guidelines for mesenchymal stromal cell-based therapeutics

Cytotherapy. 2024 Oct 29:S1465-3249(24)00903-4. doi: 10.1016/j.jcyt.2024.10.008. Online ahead of print.

Authors

Laurent Renesme¹, Kelly D Cobey², Manoj M Lalu³, Tania Bubela⁴, Raghavan Chinnadurai⁵, John De Vos⁶, Rod Dunbar⁷, Dean Fergusson⁸, Daniel Freund⁹, Jacques Galipeau¹⁰, Edwin Horwitz¹¹, Maxime Lê¹², Michael Matthay¹³, David Moher¹⁴, Jan Nolta¹⁵, Graham Parker¹⁶, Donald G Phinney¹⁷, Mahendra Rao¹⁸, John E J Rasko¹⁹, Patricia R M Rocco²⁰, Fabio Rossi²¹, Michael Rosu Myles²², Sowmya Viswanathan²³, Bernard Thébaud²⁴

Affiliations

¹ Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Canada; Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
² University of Ottawa Heart Institute, Ottawa, Canada.
³ Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada; Clinical Epidemiology Program and Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
⁴ Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
⁵ Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, Georgia, USA.
⁶ Institute for Regenerative Medicine and Biotherapy, Montpellier University, Montpellier, France.
⁷ School of Biological Sciences and Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand.
⁸ Department of Medicine, University of Ottawa, Ottawa, Canada; Ottawa Hospital Research Institute, Ottawa, Canada.
⁹ Department of Neonatology and Pediatric Critical Care Medicine, Dresden University of Technology, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany.
¹⁰ University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
¹¹ Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
¹² Patient Partner, Ottawa Hospital Research Institute, Ottawa, Canada.
¹³ Cardiovascular Research Institute, Departments of Medicine and Anesthesia, University of California, San Francisco, California, USA.
¹⁴ Ottawa Methods Centre, Ottawa Hospital Research Institute, Ottawa, Canada.
¹⁵ Institute for Regenerative Cures, University of California Davis Health, Sacramento, California, USA.
¹⁶ Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, USA.
¹⁷ Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida, USA.
¹⁸ Vita Therapeutics, Baltimore, Maryland, USA.
¹⁹ Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
²⁰ Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
²¹ Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
²² Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, Canada.
²³ Schroeder Arthritis Institute, University Health Network, Toronto, Canada; Krembil Research Institute, University Health Network, Toronto, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada.
²⁴ Sinclair Center for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Canada; Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada. Electronic address: [email protected].

PMID: 39580717
DOI: 10.1016/j.jcyt.2024.10.008

Abstract

Background aims: Despite promising results in pre-clinical studies, mesenchymal stromal cells (MSCs) face significant challenges in clinical translation. A scoping review by our group highlighted two key issues contributing to this gap: (i) lack of a clear and consensus definition for MSCs and (ii) under-reporting of critical parameters in MSC clinical studies. To address these issues, we conducted a modified Delphi study to establish and implement a consensus definition for MSCs and develop reporting guidelines for MSC clinical studies.

Methods: A steering committee of 22 international experts, including stakeholders from different MSC research fields, participated in the three Delphi rounds. For the first round, to obtain a broad perspective, additional investigators recommended by the steering committee were invited to participate. The first two rounds consisted of online surveys, whereas the third round took the form of a virtual meeting. Participants were asked to rate a series of potential defining characteristics of MSCs and items for reporting guidelines. Consensus was defined as at least 80% of the participants rating the item in the same category of importance.

Results: Eighty-seven international participants participated in the first round survey (spring 2023), 17 participants participated in the second online survey (fall 2023) and 15 participants participated in the final virtual consensus meeting (January 2024). For the MSC definition, 20 items were considered and nine reached consensus. Items included terminology (one item), cell marker expression (five items), tissue origin (one item), stemness (one item) and description of critical quality attributes (one item). For the reporting guidelines, with the 28 initial items and the additional items suggested during round 1, a total of 33 items to report were included. This included items on MSC intervention group and control (e.g., MSC product, dose and administration), MSC characteristics (e.g., MSC provenance, "fitness," viability and immune compatibility) and MSC culture conditions (e.g., oxygen environment, culture medium and use of serum).

Conclusions: By applying a Delphi method to establish a consensus definition for MSCs and reporting guidelines for MSC-based clinical trials, this work represents a significant advance in improving transparency and reproducibility in the conduct and reporting of MSC research.

Keywords: Delphi method; consensus definition; mesenchymal stromal cells; reporting guidelines.