Impact of C3G on hematopoiesis after chemotherapy: effects on hematopoietic precursors and megakaryocyte niche function
Óscar Herranz Varea
Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca)
After bone marrow (BM) depletion induced by chemotherapy, hematopoietic stem cell (HSC) self-renewal and differentiation are triggered to restore BM homeostasis through a process tightly regulated by their microenvironment, known as “niche”. Within this niche, megakaryocytes (MKs) and bone marrow adipocytes (BMAs) act with opposing roles. C3G, an activator of Rap1, has been described to affect megakaryopoiesis. However, its role in BM recovery following myelosuppression remains unexplored.
In this study, we used various mouse models to investigate the role of C3G in BM recovery after myeloablation induced by 5-fluorouracil (5-FU). These models included specific overexpression or deletion of C3G in MKs, as well as deletion of C3G directly in HSCs. This approach allowed us to explore the impact of C3G on megakaryocyte functions within the BM niche and its direct effects on HSCs. We found that MK C3G levels were inversely correlated with the number of MKs present in the BM during recovery. Conversely, BMAs decreased or increased in parallel with C3G expression in MKs. Using an indirect co-culture system with pre-adipocyte 3T3-L1 cells, we demonstrated that these changes were due to cues from MKs. Consequently, the HSC compartment was affected by C3G modulation in MKs, with progenitors predisposed to the myeloid lineage when C3G was overexpressed. Additionally, C3G deletion in HSCs led to elevated white blood cell and red blood cell counts, along with increased mean corpuscular volume and hemoglobin levels during the recovery from myeloablation. Common lymphoid progenitors and CD8 + T lymphocytes were proportionally reduced. Together, this phenotype resembled polycythemia vera, a type of myeloproliferative neoplasm (MPN).
In summary, C3G alterations in hematopoietic cells result in defective recovery following an insult, such as chemotherapeutic myeloablation with 5-FU. This primarily affects the myeloid-lymphoid balance, possibly through dysregulation of the c-Mpl pathway. These findings suggest a potential role for C3G in pathologies where this signaling is impaired, such as MPNs, making C3G a potential therapeutic target for these conditions.