Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes.

Most phenotype-associated genetic variants map to non-coding regulatory regions of the human genome. Moreover, variants associated with blood cell phenotypes are enriched in regulatory regions active during hematopoiesis. To systematically explore the nature of these regions, we developed a highly efficient strategy, Perturb-multiome, that makes it possible to simultaneously profile both chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of a range of master transcription factors (TFs). This approach allowed us to examine the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within the TF-sensitive accessible chromatin regions, while representing less than 0.3% of the genome, show a ~100-fold enrichment in heritability across certain blood cell phenotypes; this enrichment is strikingly higher than for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.

Targeting the Immune System With Mesenchymal Stromal Cell-Derived Extracellular Vesicles: What Is the Cargo's Mechanism of Action?

The potent immunomodulatory activities displayed by mesenchymal stromal cells (MSCs) have motivated their application in hundreds of clinical trials to date. In some countries, they have subsequently been approved for the treatment of immune disorders such as Crohn's disease and graft-versus-host disease. Increasing evidence suggests that their main mechanism of action in vivo relies on paracrine signaling and extracellular vesicles. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) play a prominent role in intercellular communication by allowing the horizontal transfer of microRNAs, mRNAs, proteins, lipids and other bioactive molecules between MSCs and their targets. However, despite the considerable momentum gained by MSC-EV research, the precise mechanism by which MSC-EVs interact with the immune system is still debated. Available evidence is highly context-dependent and fragmentary, with a limited number of reports trying to link their efficacy to specific active components shuttled within them. In this concise review, currently available evidence on the molecular mechanisms underlying the effects of MSC-EV cargo on the immune system is analyzed. Studies that pinpoint specific MSC-EV-borne mediators of immunomodulation are highlighted, with a focus on the signaling events triggered by MSC-EVs in target immune cells. Reports that study the effects of preconditioning or "licensing" in MSC-EV-mediated immunomodulation are also presented. The need for further studies that dissect the mechanisms of MSC-EV cargo in the adaptive immune system is emphasized. Finally, the major challenges that need to be addressed to harness the full potential of these signaling vehicles are discussed, with the ultimate goal of effectively translating MSC-EV treatments into the clinic.