Transcriptomics uncovers substantial variability associated with alterations in manufacturing processes of macrophage cell therapy products.

Gene expression plasticity is central for macrophages' timely responses to cues from the microenvironment permitting phenotypic adaptation from pro-inflammatory (M1) to wound healing and tissue-regenerative (M2, with several subclasses). Regulatory macrophages are a distinct macrophage type, possessing immunoregulatory, anti-inflammatory, and angiogenic properties. Due to these features, regulatory macrophages are considered as a potential cell therapy product to treat clinical conditions, e.g., non-healing diabetic foot ulcers. In this study we characterized two differently manufactured clinically relevant regulatory macrophages, programmable cells of monocytic origin and comparator macrophages (M1, M2a and M0) using flow-cytometry, RT-qPCR, phagocytosis and secretome measurements, and RNA-Seq. We demonstrate that conventional phenotyping had a limited potential to discriminate different types of macrophages which was ameliorated when global transcriptome characterization by RNA-Seq was employed. Using this approach we confirmed that macrophage manufacturing processes can result in a highly reproducible cell phenotype. At the same time, minor changes introduced in manufacturing resulted in phenotypically and functionally distinct regulatory macrophage types. Additionally, we have identified a novel constellation of process specific biomarkers, which will support further clinical product development.

Health-related and sociodemographic risk factors for disability pension due to low back disorders: a 30-year prospective Finnish Twin Cohort Study.

OBJECTIVES: To investigate health-related and sociodemographic risk factors for disability pensions (DP) due to low back disorders (LBD). METHODS: Questionnaire data in 1975 of the Finnish Twin Cohort Study with record linkage to information on DP due to LBD from the official pension registers during follow-up 1975 to 2004 was analyzed with Cox proportional hazard models. RESULTS: Musculoskeletal pain (Hazards Ratio [HR] = 2.36 to 2.39; 95% CI 1.97 to 2.88), smoking (HR = 1.82; 1.49 to 2.22), frequent analgesics use (HR = 1.67; 1.38 to 2.02), and presence of other chronic disease (HR = 1.44; 1.22 to 1.70) increased the risk for DP due to LBD. Years of education decreased the risk (HR = 0.81; 0.77 to 0.85). Associations remained significant when adjusted for familial background. CONCLUSIONS: Health-related and sociodemographic risk factors for DP due to LBD can be identified early in life, and they seem independent from familial effects.