3036 – BONE MARROW TRANSPLANTATION COMPROMISES THE REGENERATIVE CAPACITY OF THE BONE MARROW NICHE

Successful tissue regeneration depends on the regenerative potential of the graft and its integration in recipients tissue. In bone marrow transplantation (BMT), age-related factors negatively impact on BMT. To dissect the separate contributions of recipient conditioning and aging for the success of BMT, we compared in vitro behavior and transcriptomes of multipotent stromal cells (MSCs) from young (Y: 3 months old), middle aged mice (A: 13 months old) with mice 10 months after BMT (BMT; total age of 13 months). Our experiments show that although HSC numbers are similar in A, and BMT mice, repopulating activity is significantly reduced in BMT HSC. This is accompanied by a reduction of (CD45/Ter119) - CD31 - CD166 - SCA1 + MSCs in the BM with a strongly reduced CFU-F frequency, indicating a functional compromise of BMT MSC. On the cellular level, BMT MSC show a reduced number of mitochondria with increased ROS production compared to A mice. In addition, BMT MSC show disorganized F-actin stress fibers compared to both Y and A MSC. To understand the mechanisms underlying the compromised function of BMT MSC, we analyzed the transcriptome of uncultured primary MSCs from the BM of Y, A, and BMT mice. These analyses show that in comparison to Y and A MSC, BMT MSC downregulate genes involved in intracellular nutrient transport and mitochondrial clearance, but upregulate metabolic processes, lysosomal genes and calcium-dependent non-canonical Wnt signaling. In experiments to assess similar changes in human BMT MSC, we found that MSC from patients undergoing BMT (2 and 4 weeks after BMT) show a severe dysregulation of F-Actin organization, compared to MSC from young and aged healthy donors (HD). Our results show deregulation of HSCs and MSCs in murine or human recipients undergoing BMT. Our results further suggest underlying defects in mitochondrial clearance and metabolic activation with deregulated F-actin organization. Our findings help to dissect and understand mechanisms of age-related factors hampering BMT and could help in devising strategies to improve long-term restoration of tissues after transplantation in aging graft recipients.