Mesenchymal Stromal Cell Manufacturing for the Identification of Immunomodulatory Properties In Acute Respiratory Distress Syndrome (ARDS)
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Jimenez, Angela C.
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Abstract
The transition from traditional pharmacological drugs to cell therapies as living medicines has been highly explored in recent years. Cell therapies can originate from various sources in the body. However, they must undergo a series of processing including in vitro expansion to produce a therapeutic dose. As a result, the inherent variability existing between donors, cell sources, and expansion methods has yielded heterogeneous responses in clinical settings. Within cell therapies, mesenchymal stromal cells (MSCs) have been clinically investigated for their anti-inflammatory and tissue repair capabilities, mediated by paracrine signaling and cell-cell contact. Yet, clinical translation is limited by non-standardized and complex manufacturing processes and a lack of well-defined critical quality attributes (CQAs). More specifically, there is a need to develop non-destructive analytical techniques to monitor and identify quality attributes and critical process parameters (CPPs) during the cell manufacturing process to predict the therapeutic potency of MSCs. One disease where MSCs hold promise as a therapeutic is acute respiratory distress syndrome (ARDS), a chronic lung infection that can originate from direct lung damage, sepsis, severe pneumonia, or COVID-19. ARDS causes fluid buildup in the lungs, cell death, high levels of inflammation, and deprivation of air in the lungs, creating an immense systemic response as all tissues and organs fail to receive proper oxygenation for function. Therefore, this dissertation aims to (i) develop and employ analytical platforms to measure the metabolome and secretome of MSCs during the manufacturing process, correlate and predict MSC potency, and (ii) apply our findings to test the efficacy of MSC therapies in various developed in vitro models of ARDS. The findings of this work can lead to improvements in understanding the production of high-quality, reproducible, and therapeutic MSCs that will help realize the potential of cell-based immunotherapies for the treatment of ARDS.
Our findings showed that a novel gas chromatography mass spectrometry technique to non-destructively measure the headspace of the cell culture medium had correlations to cell expansion and potency. Using non-destructive medium sampling of MSC expansion for targeted metabolite and cytokine measurements mathematical models were able to predict potency as early as one day into the expansion. This was applied to in vitro models of ARDS where MSCs were challenged in a physiologically relevant model. From this the influence of different MSC processing parameters were unveiled. This work ultimately demonstrating the importance of defining quality attributes to improve MSC therapeutic outcomes.
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2024-04-26
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Dissertation