Targeting mitochondria mitigates chemotherapy-induced bone marrow dysfunction
Hematopoietic recovery between cycles of chemotherapy is critical for treatment continuation and outcome, and is typically determined based on neutrophil and platelet counts. Although clinically meaningful, this metric does not capture incomplete recovery of other lineages or hematopoietic stem cells (HSCs) after chemotherapy, which may have significant consequences.
To investigate this, we exposed mice to clinically relevant regimens of three different chemotherapeutic agents: Fluorouracil, Cytarabine or Doxorubicin. Peripheral blood and bone marrow were analyzed long-term after chemotherapy exposure.
Despite rapid and complete recovery of total nucleated cell counts, we observed that HSCs are significantly and durably affected by chemotherapy exposure. This lasting damage results in myeloid-skewed hematopoiesis with concomitant lymphocytopenia, anaemia, and poor engraftment upon transplantation. Notably, HSCs from chemotherapy-treated mice exhibit decreased mitochondrial content and mitochondrial membrane potential (∆ψm), simulating premature ageing. Previously, we could rescue hematopoietic ageing in mice using the mitochondria-targeted antioxidant mitoquinol (MitoQ) (Mansell, Cell Stem Cell, 2021). Strikingly, we show here that strategic MitoQ treatment did indeed rescue numerous aspects of chemotherapy-induced hematopoietic damage. Specifically, MitoQ treatment results in accelerated blood and bone marrow recovery and enhanced B-lymphopoiesis upon transplantation.
Thus, we have established herein that chemotherapy induces “clinically hidden” but significant long-term damage to blood and bone marrow that resembles premature ageing. Mitochondria-targeted treatment elicits stable changes in HSCs, resulting in a partial rescue of chemotherapy-induced premature hematopoietic ageing. This work opens up novel avenues to explore for supportive treatment of patients undergoing any type of myelo-ablative chemotherapy.