Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases
Abstract Background Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) revealed their key role in immune regulation, offering promising therapeutic perspectives for immune and inflammatory diseases. We aimed to develop a production process of an UC-MSC-based product and then to characterize...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
BMC
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/347d91d1927840198e1681f77e14c9f8 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:347d91d1927840198e1681f77e14c9f8 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:347d91d1927840198e1681f77e14c9f82021-11-14T12:08:00ZDevelopment of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases10.1186/s13287-021-02637-71757-6512https://doaj.org/article/347d91d1927840198e1681f77e14c9f82021-11-01T00:00:00Zhttps://doi.org/10.1186/s13287-021-02637-7https://doaj.org/toc/1757-6512Abstract Background Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) revealed their key role in immune regulation, offering promising therapeutic perspectives for immune and inflammatory diseases. We aimed to develop a production process of an UC-MSC-based product and then to characterize UC-MSC properties and immunomodulatory activities in vitro, related to their clinical use and finally, to transfer this technology to a good manufacturing practice (GMP) compliant facility, to manufacture an advanced therapy medicinal product (ATMP). Methods Fifteen human umbilical cords (UCs) were collected to develop the production process. Three batches of UC-MSCs from a single donor were characterized at basal state and after in vitro pro-inflammatory stimulation by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Proliferation, immunophenotype, activation markers’ expression and the inhibition of T cell proliferation were assessed. Finally, this technology was transferred to a GMP-compliant facility to manufacture an UC-MSC-based ATMP, from a single donor, using the explant method followed by the establishment of master and work cell stocks. Results Twelve UCs were processed successfully allowing to isolate UC-MSCs with doubling time and population doubling remaining stable until passage 4. CD90, CD105, CD73, CD44, CD29, CD166 expression was positive; CD14, CD45, CD31, HLA-DR, CD40, CD80 and CD86 expression was negative, while CD146 and HLA-ABC expression was heterogeneous. Cell morphology, proliferation and immunophenotype were not modified by inflammatory treatment. Indoleamine 2,3-dioxygenase (IDO) expression was significantly induced by IFNγ and IFNγ + TNFα versus non-treated cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression was induced significantly after priming. T cell proliferation was significantly decreased in the presence of UC-MSCs in a dose-dependent manner. This inhibitory effect was improved by IFNγ or IFNγ + TNFα, at UC-MSCs:PBMC ratio 1:10 and 1:30, whereas only IFNγ allowed to decrease significantly T cell proliferation at ratio 1:100. The manufacturing process of the UC-MSC-based ATMP was qualified and authorized by the French regulatory agency for clinical use (NCT04333368). Conclusion This work allowed to develop an investigational UC-MSC-based ATMP authorized for clinical use. Our results showed that an inflammatory environment preserves the biological properties of UC-MSCs with an improvement of their immunomodulatory functions.Miryam MebarkiNathan IglickiCéline MarignyCamille AbadieClaire NicoletGuillaume ChurlaudCamille MaheuxHélène BoucherAntoine MonselPhilippe MenaschéJérôme LargheroLionel FaivreAudrey CrasBMCarticleHuman umbilical cordMesenchymal stromal cellsImmunomodulationInflammationAdvanced therapy medicinal productGood manufacturing practiceMedicine (General)R5-920BiochemistryQD415-436ENStem Cell Research & Therapy, Vol 12, Iss 1, Pp 1-15 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Human umbilical cord Mesenchymal stromal cells Immunomodulation Inflammation Advanced therapy medicinal product Good manufacturing practice Medicine (General) R5-920 Biochemistry QD415-436 |
| spellingShingle |
Human umbilical cord Mesenchymal stromal cells Immunomodulation Inflammation Advanced therapy medicinal product Good manufacturing practice Medicine (General) R5-920 Biochemistry QD415-436 Miryam Mebarki Nathan Iglicki Céline Marigny Camille Abadie Claire Nicolet Guillaume Churlaud Camille Maheux Hélène Boucher Antoine Monsel Philippe Menasché Jérôme Larghero Lionel Faivre Audrey Cras Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| description |
Abstract Background Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) revealed their key role in immune regulation, offering promising therapeutic perspectives for immune and inflammatory diseases. We aimed to develop a production process of an UC-MSC-based product and then to characterize UC-MSC properties and immunomodulatory activities in vitro, related to their clinical use and finally, to transfer this technology to a good manufacturing practice (GMP) compliant facility, to manufacture an advanced therapy medicinal product (ATMP). Methods Fifteen human umbilical cords (UCs) were collected to develop the production process. Three batches of UC-MSCs from a single donor were characterized at basal state and after in vitro pro-inflammatory stimulation by interferon-γ (IFNγ) and tumor necrosis factor-α (TNFα). Proliferation, immunophenotype, activation markers’ expression and the inhibition of T cell proliferation were assessed. Finally, this technology was transferred to a GMP-compliant facility to manufacture an UC-MSC-based ATMP, from a single donor, using the explant method followed by the establishment of master and work cell stocks. Results Twelve UCs were processed successfully allowing to isolate UC-MSCs with doubling time and population doubling remaining stable until passage 4. CD90, CD105, CD73, CD44, CD29, CD166 expression was positive; CD14, CD45, CD31, HLA-DR, CD40, CD80 and CD86 expression was negative, while CD146 and HLA-ABC expression was heterogeneous. Cell morphology, proliferation and immunophenotype were not modified by inflammatory treatment. Indoleamine 2,3-dioxygenase (IDO) expression was significantly induced by IFNγ and IFNγ + TNFα versus non-treated cells. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression was induced significantly after priming. T cell proliferation was significantly decreased in the presence of UC-MSCs in a dose-dependent manner. This inhibitory effect was improved by IFNγ or IFNγ + TNFα, at UC-MSCs:PBMC ratio 1:10 and 1:30, whereas only IFNγ allowed to decrease significantly T cell proliferation at ratio 1:100. The manufacturing process of the UC-MSC-based ATMP was qualified and authorized by the French regulatory agency for clinical use (NCT04333368). Conclusion This work allowed to develop an investigational UC-MSC-based ATMP authorized for clinical use. Our results showed that an inflammatory environment preserves the biological properties of UC-MSCs with an improvement of their immunomodulatory functions. |
| format |
article |
| author |
Miryam Mebarki Nathan Iglicki Céline Marigny Camille Abadie Claire Nicolet Guillaume Churlaud Camille Maheux Hélène Boucher Antoine Monsel Philippe Menasché Jérôme Larghero Lionel Faivre Audrey Cras |
| author_facet |
Miryam Mebarki Nathan Iglicki Céline Marigny Camille Abadie Claire Nicolet Guillaume Churlaud Camille Maheux Hélène Boucher Antoine Monsel Philippe Menasché Jérôme Larghero Lionel Faivre Audrey Cras |
| author_sort |
Miryam Mebarki |
| title |
Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| title_short |
Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| title_full |
Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| title_fullStr |
Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| title_full_unstemmed |
Development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| title_sort |
development of a human umbilical cord-derived mesenchymal stromal cell-based advanced therapy medicinal product to treat immune and/or inflammatory diseases |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/347d91d1927840198e1681f77e14c9f8 |
| work_keys_str_mv |
AT miryammebarki developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT nathaniglicki developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT celinemarigny developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT camilleabadie developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT clairenicolet developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT guillaumechurlaud developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT camillemaheux developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT heleneboucher developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT antoinemonsel developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT philippemenasche developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT jeromelarghero developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT lionelfaivre developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases AT audreycras developmentofahumanumbilicalcordderivedmesenchymalstromalcellbasedadvancedtherapymedicinalproducttotreatimmuneandorinflammatorydiseases |
| _version_ |
1718429396629454848 |