3156 – BONE MARROW TRANSPLANTATION COMPROMISES THE REGENERATIVE CAPACITY OF THE NICHE

Abstract

In bone marrow transplantation (BMT), the recipient environment is conditioned by myeloablative treatment. In many patients, this is associated with long-term osteoporotic changes. To assess the contributions of recipient conditioning and aging of the niche, we compared multipotent stromal and progenitor cells (MSPCs) from young (young: 3 mo old), middle-aged mice (aged: 13 mo old) with mice 10 months after BMT (BMT; total age of 13 mo). Our experiments show reduced numbers of (CD45/Ter119)- CD31- CD166low/med SCA1+ MSPCs with a strongly reduced CFU-F frequency, suggesting a functional compromise of MSPC in BMT. On the cellular level, BMT MSPCs show an increased ROS production compared to aged and young mice. In addition, BMT MSPC show disorganized F-actin stress fibers with increased activation of the small GTPase CDC42 compared to both young and aged MSPCs. In experiments with patient-derived human BMT MSPC, we found similar deregulation of F-Actin, compared to MSPC from young and aged healthy donors (HD). To prevent damaging functional and cytoskeletal changes after conditioning, we treated a small cohort of control and BMT mice with CASIN, an inhibitor of CDC42, in the first week after transplantation. This resulted in a 1.2-fold higher engraftment without affecting early regeneration. Interestingly, CASIN-treated male BMT mice also show elevated trabecular separation and thickness with a slightly higher bone volume compared to treated controls. Our results show that early CASIN-treatment after BMT increases osteogenesis and reduces osteoporotic changes commonly noted in human patients after BMT. Our findings could help in devising strategies to improve long-term restoration of tissues after transplantation, particularly in aging graft recipients. In bone marrow transplantation (BMT), the recipient environment is conditioned by myeloablative treatment. In many patients, this is associated with long-term osteoporotic changes. To assess the contributions of recipient conditioning and aging of the niche, we compared multipotent stromal and progenitor cells (MSPCs) from young (young: 3 mo old), middle-aged mice (aged: 13 mo old) with mice 10 months after BMT (BMT; total age of 13 mo). Our experiments show reduced numbers of (CD45/Ter119)- CD31- CD166low/med SCA1+ MSPCs with a strongly reduced CFU-F frequency, suggesting a functional compromise of MSPC in BMT. On the cellular level, BMT MSPCs show an increased ROS production compared to aged and young mice. In addition, BMT MSPC show disorganized F-actin stress fibers with increased activation of the small GTPase CDC42 compared to both young and aged MSPCs. In experiments with patient-derived human BMT MSPC, we found similar deregulation of F-Actin, compared to MSPC from young and aged healthy donors (HD). To prevent damaging functional and cytoskeletal changes after conditioning, we treated a small cohort of control and BMT mice with CASIN, an inhibitor of CDC42, in the first week after transplantation. This resulted in a 1.2-fold higher engraftment without affecting early regeneration. Interestingly, CASIN-treated male BMT mice also show elevated trabecular separation and thickness with a slightly higher bone volume compared to treated controls. Our results show that early CASIN-treatment after BMT increases osteogenesis and reduces osteoporotic changes commonly noted in human patients after BMT. Our findings could help in devising strategies to improve long-term restoration of tissues after transplantation, particularly in aging graft recipients.