Optimization of Mesenchymal Stromal Cell (MSC) Manufacturing Processes for a Better Therapeutic Outcome

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Abstract

MSCs products as well as their derived extracellular vesicles, are currently being explored as advanced biologics in cell-based therapies with high expectations for their clinical use in the next few years. In recent years, various strategies designed for improving the therapeutic potential of mesenchymal stromal cells (MSCs), including pre-conditioning for enhanced cytokine production, improved cell homing and strengthening of immunomodulatory properties, have been developed but the manufacture and handling of these cells for their use as advanced therapy medicinal products (ATMPs) remains insufficiently studied, and available data are mainly related to non-industrial processes. In the present article, we will review this topic, analyzing current information on the specific regulations, the selection of living donors as well as MSCs from different sources (bone marrow, adipose tissue, umbilical cord, etc.), in-process quality controls for ensuring cell efficiency and safety during all stages of the manual and automatic (bioreactors) manufacturing process, including cryopreservation, the use of cell banks, handling medicines, transport systems of ATMPs, among other related aspects, according to European and US legislation. Our aim is to provide a guide for a better, homogeneous manufacturing of therapeutic cellular products with special reference to MSCs.

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Most cited references 126

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Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

M Dominici, K Le Blanc, I Mueller … (2006)

The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.

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Extracellular vesicles: Exosomes, microvesicles, and friends

Graça Raposo, Willem Stoorvogel (2013)

Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

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Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue.

Susanne Kern, Hermann Eichler, Johannes Stoeve … (2006)

Mesenchymal stem cells (MSCs) represent a promising tool for new clinical concepts in supporting cellular therapy. Bone marrow (BM) was the first source reported to contain MSCs. However, for clinical use, BM may be detrimental due to the highly invasive donation procedure and the decline in MSC number and differentiation potential with increasing age. More recently, umbilical cord blood (UCB), attainable by a less invasive method, was introduced as an alternative source for MSCs. Another promising source is adipose tissue (AT). We compared MSCs derived from these sources regarding morphology, the success rate of isolating MSCs, colony frequency, expansion potential, multiple differentiation capacity, and immune phenotype. No significant differences concerning the morphology and immune phenotype of the MSCs derived from these sources were obvious. Differences could be observed concerning the success rate of isolating MSCs, which was 100% for BM and AT, but only 63% for UCB. The colony frequency was lowest in UCB, whereas it was highest in AT. However, UCB-MSCs could be cultured longest and showed the highest proliferation capacity, whereas BM-MSCs possessed the shortest culture period and the lowest proliferation capacity. Most strikingly, UCB-MSCs showed no adipogenic differentiation capacity, in contrast to BM- and AT-MSCs. Both UCB and AT are attractive alternatives to BM in isolating MSC: AT as it contains MSCs at the highest frequency and UCB as it seems to be expandable to higher numbers.

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Author and article information

Contributors

Maria Eugenia Fernández-Santos: URI : https://loop.frontiersin.org/people/1027704

Mariano Garcia-Arranz: URI : https://loop.frontiersin.org/people/718749

Pilar Sepúlveda: URI : https://loop.frontiersin.org/people/568127

Francisco Fernández-Avilés: URI : https://loop.frontiersin.org/people/721993

Felipe Prosper: URI : https://loop.frontiersin.org/people/739114

Fermin Sánchez-Guijo: URI : https://loop.frontiersin.org/people/704778

Jose M. Moraleda: URI : https://loop.frontiersin.org/people/886868

Agustin G. Zapata: URI : https://loop.frontiersin.org/people/189722

Journal

Journal ID (nlm-ta): Front Immunol

Journal ID (iso-abbrev): Front Immunol

Journal ID (publisher-id): Front. Immunol.

Title: Frontiers in Immunology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-3224

Publication date (Electronic): 09 June 2022

Publication date Collection: 2022

Volume: 13

Electronic Location Identifier: 918565

Affiliations

[1] ¹ Cardiology Department, HGU Gregorio Marañón. GMP-ATMPs Production Unit, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM). Complutense University, CIBER Cardiovascular (CIBERCV), ISCIII , Madrid, Spain

[2] ² Platform GMP Units from TerCel and TERAV Networks. RETIC TerCel & RICORS TERAV, ISCIII , Madrid, Spain

[3] ³ New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD). Surgery Department, Autonoma University of Madrid , Madrid, Spain

[4] ⁴ Hematology Department and Cell Therapy Area, Clínica Universidad de Navarra. CIBEROC and IDISNA , Pamplona, Spain

[5] ⁵ Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Virgen de la Arrixaca University Hospital, University of Murcia , Murcia, Spain

[6] ⁶ Cell Therapy Area and Hematology Department, IBSAL-University Hospital of Salamanca, University of Salamanca , Salamanca, Spain

[7] ⁷ Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe , Valencia, Spain

[8] ⁸ Department of Cell Biology, Complutense University , Madrid, Spain

Author notes

Edited by: Guido Moll, Charité Universitätsmedizin Berlin, Germany

Reviewed by: Takeo Mukai, The University of Tokyo, Japan; Clara Sanz-Nogues, National University of Ireland Galway, Ireland

*Correspondence: Maria Eugenia Fernández-Santos, mariuge@ 123456fibhgm.org ; Agustin G. Zapata, zapata@ 123456bio.ucm.es

†These authors have contributed equally to this work and share first authorship

This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

Article

DOI: 10.3389/fimmu.2022.918565

PMC ID: 9261977

PubMed ID: 35812460

SO-VID: 417a8edc-f1b9-44c9-abf6-74659e00e420

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 12 April 2022

Date accepted : 10 May 2022

Page count

Figures: 2, Tables: 2, Equations: 0, References: 127, Pages: 19, Words: 12694

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Optimization of Mesenchymal Stromal Cell (MSC) Manufacturing Processes for a Better Therapeutic Outcome

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Journal of Circulating Biomarkers

Most cited references 126

Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

Extracellular vesicles: Exosomes, microvesicles, and friends

Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue.

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Cited by 32

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