PROJECT SUMMARY The objective of the proposed research supplement is to understand how donor biologic sex impacts the level and functionality of surface protein, CD73, on human mesenchymal stem cells (hMSCs). This protein is essential in the metabolism of adenosine diphosphate (ADP) to anti-inflammatory adenosine (ADO). Some mechanisms underlying the immunomodulatory capabilities have been well described such as cytokine production, but others such as purine metabolism are understudied. We aim to understand the difference in purine metabolism by CD73 through the lens of donor sex in order to assess efficacy of hMSCs to mitigate an inflammatory state. hMSCs are able to mitigate inflammation in many disease states but have shown variability between donors in clinical trials. Our study will investigate how donor sex plays a role in CD73 expression, CD73 activity level, and cytokine production, another mechanism of hMSC action in vivo. Together these data will provide critical insight into sex- dependent differences in hMSC immunomodulation. This work is of importance because it will impact clinical application of hMSCs by (1) evaluation of cells for specific therapeutic applications, (2) selection of allogenic donors for broad application, (3) selecting candidates that would benefit from autologous hMSC therapeutics.