Mesenchymal stem/stromal cells (MSCs) hold great promise for the treatment of autoimmune conditions given their immunomodulatory properties. Based on the low immunogenicity of MSCs, it is tempting to consider the expansion of MSCs from a “universal donor” in culture prior to their allogeneic applications for immediate care. This raises the critical question of the criteria we should use to select the best “universal donor”. It is also imperative we compare the “universal” approach with a “personalized” one for clinical value. In addition to the call for MHC-matching, recent studies suggest that factors including age, sex, and biological sources of MSCs can have significant impact on therapy outcome. Here, we will review findings from these studies, which shed light on the variables that can guide the important choice of “universal” or “personalized” MSC therapy for autoimmune diseases. Cells, 11(13). doi 10.3390/cells11132077.
Autoimmune diseases affect 7.5% of the US population, and they are among the leading causes of death and disability. A notable feature of many autoimmune diseases is their greater prevalence in females than in males, but the underlying mechanisms of this have remained unclear. Through the use of high-resolution global transcriptome analyses, we demonstrated a female-biased molecular signature associated with susceptibility to autoimmune disease and linked this to extensive sex-dependent co-expression networks. This signature was independent of biological age and sex-hormone regulation and was regulated by the transcription factor VGLL3, which also had a strong female-biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases, including lupus, scleroderma and Sjögren's syndrome, and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identified a VGLL3-regulated network as a previously unknown inflammatory pathway that promotes female-biased autoimmunity. They demonstrate the importance of studying immunological processes in females and males separately and suggest new avenues for therapeutic development. Nat Immunol,18(2):152-160.
Sexual dimorphism is exhibited remarkably in the female predominance of autoimmune diseases (e.g. systemic lupus erythematosus, female-to-male ratio 9 : 1). To understand the female bias in autoimmunity, we focused on vestigial-like family member 3 (VGLL3), a molecule with increased expression in females and known to promote autoimmunity. We report that VGLL3 mediates the cellular stress response by upregulating p53 and IL-17C. Energy stress allows VGLL3 to be induced by IFNα, which ultimately leads to p53-dependent, lupus-associated, inflammatory cell death. Our results suggest that female-biased expression of VGLL3 helps cells adapt to metabolic stress, which, intriguingly, is known as a significant challenge during the evolution of placental mammals due to the need to feed a developing embryo. The findings also uncover the importance of maintaining metabolic homeostasis in the prevention of autoimmunity. FEBS Lett, 594(20): 3371-3383.
The PD-L1/2–PD-1 immune checkpoint is essential for the proper induction of peripheral tolerance and limits autoimmunity, whereas tumor cells exploit their expression to promote immune evasion. Many different cell types express PD-L1/2, either constitutively or upon stimulation, but the factors driving this expression are often poorly defined. In this study, using genome-wide CRISPR activation screening, we identified three factors that upregulate PD-L1 expression: GATA2, MBD6, and transcription cofactor vestigial-like protein 3 (VGLL3). VGLL3 acts as a transcriptional regulator, and its expression induced PD-L1 in many different cell types. Conversely, loss of VGLL3 impaired IFN-γ–induced PD-L1/2 expression in human keratinocytes. Mechanistically, by performing a second screen to identify proteins acting in concert with VGLL3, we found that VGLL3 forms a complex with TEAD1 and RUNX1/3 to drive expression of PD-L1/2. Collectively, our work identified a new transcriptional complex controlling PD-L1/2 expression and suggests that VGLL3, in addition to its known role in the expression of proinflammatory genes, can balance inflammation by upregulating the anti-inflammatory factors PD-L1 and PD-L2. J Immunol, 209(5):907-915.
Sexual dimorphism is exhibited remarkably in the female predominance of autoimmune diseases (e.g. systemic lupus erythematosus, female-to-male ratio 9 : 1). To understand the female bias in autoimmunity, we focused on vestigial-like family member 3 (VGLL3), a molecule with increased expression in females and known to promote autoimmunity. We report that VGLL3 mediates the cellular stress response by upregulating p53 and IL-17C. Energy stress allows VGLL3 to be induced by IFNα, which ultimately leads to p53-dependent, lupus-associated, inflammatory cell death. Our results suggest that female-biased expression of VGLL3 helps cells adapt to metabolic stress, which, intriguingly, is known as a significant challenge during the evolution of placental mammals due to the need to feed a developing embryo. The findings also uncover the importance of maintaining metabolic homeostasis in the prevention of autoimmunity. J Mol Med, 100(9):1253-1265.