Human bone marrow-derived, pooled, allogeneic mesenchymal stromal cells manufactured from multiple donors at different times show comparable biological functions in vitro, and in vivo to repair limb ischemia
| Autor: | Siddikuzzaman, Pawan Gupta, Priyanka Swamynathan, Charan Thej, Mathiyazhagan Rengasamy, Raviraja N. Seetharam, Ankita Walvekar, Sudha Balasubramanian, Pradnya Shahani, Anish Sen Majumdar, Udaykumar Kolkundkar, Swathi Sundar Raj |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cell type Medicine (General) Necrosis Population Ischemia Hind limb ischemia Mice Nude Neovascularization Physiologic Medicine (miscellaneous) QD415-436 030204 cardiovascular system & hematology Mesenchymal Stem Cell Transplantation Biochemistry Genetics and Molecular Biology (miscellaneous) Biochemistry Mice 03 medical and health sciences 0302 clinical medicine R5-920 Bone Marrow In vivo medicine Animals Humans Tissue Distribution education Mice Inbred BALB C education.field_of_study business.industry Stempeucel® Research Pooled mesenchymal stromal cells Mesenchymal stem cell Hematopoietic Stem Cell Transplantation Mesenchymal Stem Cells Cell Biology Critical limb ischemia medicine.disease Hindlimb Multiple bone marrow aspirations 030104 developmental biology Cancer research Molecular Medicine Angiogenesis Stem cell medicine.symptom business |
| Zdroj: | Stem Cell Research & Therapy, Vol 12, Iss 1, Pp 1-16 (2021) Stem Cell Research & Therapy |
| ISSN: | 1757-6512 |
| Popis: | Background We have previously demonstrated that a pooled population of bone marrow-derived, allogeneic mesenchymal stromal cells (BMMSC), Stempeucel®-1, produced under good manufacturing practices (GMP) conditions, showed clinical efficacy and safety in patients suffering from critical limb ischemia (CLI) due to Buerger’s disease. While Stempeucel®-1 is currently used for CLI and other clinical indications, we wanted to ensure that the product’s continuity is addressed by developing and characterizing a second generation of pooled product (Stempeucel®-1A), manufactured identically from second BM aspirates of the same three donors after a 2-year interval. Methods The two versions of Stempeucel® were manufactured and subjected to gene and protein expression analysis. The nature of various growth factors/cytokines secreted and immunomodulatory activity of these two cell populations were compared directly by various in vitro assays. The preclinical efficacy of these two cell types was compared in an experimental model of hind limb ischemia (HLI) in BALB/c nude mice. The reversal of ischemia, blood flow, and muscle regeneration were determined by functional scoring, laser Doppler imaging, and immunohistochemical analyses. Results Qualitative and quantitative analyses of genes and proteins involved in promoting angiogenic activity and immune regulatory functions revealed high levels of correlation between Stempeucel®-1 and Stempeucel®-1A cell populations. Moreover, intramuscular (i.m) administration of these two cell products in the ischemic limbs of BALB/c nude mice showed significant repair (≥ 70%) of toe and foot necrosis, leading to improved ambulatory function and limb salvage. Furthermore, a biodistribution kinetics study showed that Stempeucel®-1 was mostly localized in the ischemic muscles of mice for a significantly longer time compared to normal muscles, thus playing an essential role in modulating and reversing HLI damage. Conclusions This study shows that with a reproducible manufacturing procedure, it is possible to generate large numbers of pooled mesenchymal stromal cells from human bone marrow samples to establish product equivalence. We conclude from these results that, for the first time, two pooled, allogeneic BMMSC products can be repeatedly manufactured at different time intervals using a two-tier cell banking process with robust and comparable angiogenic properties to treat ischemic diseases. |
| Databáze: | OpenAIRE |
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