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首页> 外文会议>Conference on advancing manufacture of cell and gene therapies >SCALABLE EXPANSION OF HUMAN UMBILICAL CORD MATRIX- AND ADIPOSE TISSUE-DERIVED MESENCHYMAL STEM/STROMAL CELLS AND DERIVED EXOSOMES IN THE SINGLE-USE, VERTICAL-WHEEL BIOREACTOR SYSTEM USING A HUMAN PLATELET LYSATE CULTURE SUPPLEMENT
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SCALABLE EXPANSION OF HUMAN UMBILICAL CORD MATRIX- AND ADIPOSE TISSUE-DERIVED MESENCHYMAL STEM/STROMAL CELLS AND DERIVED EXOSOMES IN THE SINGLE-USE, VERTICAL-WHEEL BIOREACTOR SYSTEM USING A HUMAN PLATELET LYSATE CULTURE SUPPLEMENT

机译：单次使用垂直轮生物反应器系统中人类脐带基质和脂肪组织来源的间充质干细胞/基质细胞和衍生的外来体的可扩展性，使用人类血小板裂解液培养物

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Mesenchymal stem/stromal cells (MSC) hold great promise for tissue engineering and regenerative medicine settings due to their multilineage differentiation potential and their intrinsic immunomodulatory and trophic activities. Large cell doses (>1×10~6 cells/kg) are however required for clinical implementation and the success in obtaining those cell numbers is dependent on efficient ex vivo expansion protocols able to comply with Good Manufacturing microcarrier-based cultures in scalable bioreactors using serum-/xenogeneic-free (S/XF) culture components. In this context, a S/XF microcarrier-based culture system was successfully established for the expansion of human UCM and AT MSC using an innovative disposable bioreactor system utilizing the Vertical-Wheel™ technology (PBS-0.1 MAG with maximum working volume of 100 mL, PBS Biotech) combined with a commercially available fibrinogen-depleted human platelet lysate-based culture supplement (UltraGRO™-PURE, AventaCell BioMedical). By optimizing the agitation and feeding regimes, UCM and AT MSC were successfully expanded to maximum cell densities of 5.3 ± 0.4 × 10~5 cell/mL (n=3) and 3.6 ± 0.7 × 10~5 cell/mL (n=3), respectively, after 7 days of culture (cell viability ≥: 94%), while maintaining their identity. Recently, increasing evidence has proposed extracellular vesicles (EVs), as exosomes, as mediators of many of the MSC-associated therapeutic features. Exosomes are small EVs (30-150nm) of endocytic origin, involved in intercellular.communication, through transfer of a cargo of proteins and RNAs. In this context, the platform established for the expansion of MSC is under optimization for exosome production. Dynamic culture systems, as the one presented herein, are expected to allow a higher exosome titer, as well as a better control when fine-tuning the exosomes' properties, by changing culture conditions (e.g. shear, oxygen). Preliminary results have shown that human MSC expanded in the Vertical-Wheel™ bioreactor system allowed to obtain a population of EVs with a more homogeneous size distribution profile, when compared to cells cultured in traditional static systems. Overall, we demonstrate that this culture system is able to robustly manufacture human MSC and MSC-based exosomes towards the development of novel therapeutic products.
机译：间充质干/基质细胞（MSC）由于其多系分化潜能以及其固有的免疫调节和营养活性，在组织工程和再生医学领域具有广阔的前景。然而，临床实施需要大剂量的细胞（> 1×10〜6个细胞/ kg），能否成功获得这些细胞数量取决于有效的离体扩增方案，该方案能够在可扩展的生物反应器中使用Good Manufacturing基于微载体的培养物进行培养。无血清/无异源（S / XF）培养成分。在此背景下，使用创新的一次性生物反应器系统，利用Vertical-Wheel™技术（PBS-0.1 MAG，最大工作体积为100 mL），成功建立了基于S / XF微载体的培养系统，用于扩展人UCM和AT MSC。 （PBS Biotech，PBS生物技术公司）与市售的贫纤维蛋白原的人血小板裂解物基培养补充剂（UltraGRO™-PURE，AventaCell BioMedical）结合使用。通过优化搅拌和进料方式，UCM和AT MSC成功扩展至最大细胞密度，分别为5.3±0.4×10〜5细胞/ mL（n = 3）和3.6±0.7×10〜5细胞/ mL（n = 3） ）分别培养7天后（细胞生存力≥：94％），同时保持其身份。近来，越来越多的证据提出细胞外囊泡（EVs）作为外来体，作为许多与MSC相关的治疗特征的介质。外泌体是内吞起源的小型电动汽车（30-150nm），通过转移大量蛋白质和RNA参与细胞间的通讯。在这种情况下，为外泌体生产而优化的用于MSC扩展的平台正在优化中。通过改变培养条件（例如剪切，氧气），期望动态培养系统（如本文所述的那样）允许更高的外泌体效价，以及在微调外泌体特性时更好的控制。初步结果表明，与在传统静态系统中培养的细胞相比，在Vertical-Wheel™生物反应器系统中扩增的人MSC能够获得具有更均一的尺寸分布特征的EV群体。总体而言，我们证明了这种培养系统能够稳固地制造人类MSC和基于MSC的外来体，从而开发出新型治疗产品。

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