Strategies to enhance immunomodulatory properties and reduce heterogeneity in mesenchymal stromal cells during ex vivo expansion.

Therapies using mesenchymal stromal cells (MSCs) to treat immune and inflammatory conditions are now at an exciting stage of development, with many MSC-based products progressing to phase II and III clinical trials. However, a major bottleneck in the clinical translation of allogeneic MSC therapies is the variable immunomodulatory properties of MSC products due to differences in their tissue source, donor heterogeneity and processes involved in manufacturing and banking. This variable functionality of MSC products likely contributes to the substantial inconsistency observed in the clinical outcomes of phase III trials of MSC therapies; several trials have failed to reach the primary efficacy endpoint. In this review, we discuss various strategies to consistently maintain or enhance the immunomodulatory potency of MSCs during ex vivo expansion, which will enable the manufacture of allogeneic MSC banks that have high potency and low variability. Biophysical and biochemical priming strategies, the use of culture additives such as heparan sulfates, and genetic modification can substantially enhance the immunomodulatory properties of MSCs during in vitro expansion. Furthermore, robust donor screening, the use of biomarkers to select for potent MSC subpopulations, and rigorous quality testing to improve the release criteria for MSC banks have the potential to reduce batch-to-batch heterogeneity and enhance the clinical efficacy of the final MSC product. Machine learning approaches to develop predictive models of individual patient response can enable personalized therapies and potentially establish correlations between in vitro potency measurements and clinical outcomes in human trials.

Cultivated meat: research opportunities to advance cell line development.

Cultivated meat offers an avenue to feed a growing population and reduce environmental burdens associated with conventional meat production. In this Science & Society paper, we outline challenges the industry is facing in obtaining robust cell lines for the development of cultivated meat products. Through an industry survey, several knowledge gaps in cell biology were identified and are presented as research opportunities here. Continued fundamental research is essential to enhance the availability of suitable cell lines and enable cost-effective and large-scale manufacture of cultivated meat.

Age-Related Changes in the Inflammatory Status of Human Mesenchymal Stem Cells: Implications for Cell Therapy.

Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre-clinical culture expansion inevitably drives cells toward replicative "aging" and a consequent decline in quality. These "in vitro-aged" hMSCs resemble biologically aged cells, which have been reported to show senescence signatures, diminished immunosuppressive capacity, and weakened regenerative potential as well as pro-inflammatory features. In this review, we have surveyed the literature to explore the intimate relationship between the inflammatory status of hMSCs and their in vitro aging process. We posit that a shift from an anti-inflammatory to a pro-inflammatory phenotype of culture-expanded hMSCs contributes to a deterioration in their therapeutic efficacy. Potential molecular and cellular mechanisms underpinning this phenomenon have been discussed. We have also highlighted studies that leverage these mechanisms to make culture-expanded hMSCs more amenable for clinical use.

Heparan Sulfate Proteoglycans: Key Mediators of Stem Cell Function.

Heparan sulfate proteoglycans (HSPGs) are an evolutionarily ancient subclass of glycoproteins with exquisite structural complexity. They are ubiquitously expressed across tissues and have been found to exert a multitude of effects on cell behavior and the surrounding microenvironment. Evidence has shown that heterogeneity in HSPG composition is crucial to its functions as an essential scaffolding component in the extracellular matrix as well as a vital cell surface signaling co-receptor. Here, we provide an overview of the significance of HSPGs as essential regulators of stem cell function. We discuss the various roles of HSPGs in distinct stem cell types during key physiological events, from development through to tissue homeostasis and regeneration. The contribution of aberrant HSPG production to altered stem cell properties and dysregulated cellular homeostasis characteristic of cancer is also reviewed. Finally, we consider approaches to better understand and exploit the multifaceted functions of HSPGs in influencing stem cell characteristics for cell therapy and associated culture expansion strategies.