Stem Cells: Physiology and Microenvironment Myelo-erythroid commitment after burn injury is under -adrenergic control via MafB regulation

Hasan S, Johnson NB, Mosier MJ, Shankar R, Conrad P, Szilagyi A, Gamelli RL, Muthumalaiappan K. Myelo-erythroid commitment after burn injury is under -adrenergic control via MafB regulation. Am J Physiol Cell Physiol 312: C286–C301, 2017. First published December 28, 2016; doi:10.1152/ajpcell.00139.2016.—Severely injured burn patients receive multiple blood transfusions for anemia of critical illness despite the adverse consequences. One limiting factor to consider alternate treatment strategies is the lack of a reliable test platform to study molecular mechanisms of impaired erythropoiesis. This study illustrates how conditions resulting in a high catecholamine microenvironment such as burns can instigate myelo-erythroid reprioritization influenced by -adrenergic stimulation leading to anemia. In a mouse model of scald burn injury, we observed, along with a threefold increase in bone marrow LSK cells (lin Sca1 cKit ), that the myeloid shift is accompanied with a significant reduction in megakaryocyte erythrocyte progenitors (MEPs). -Blocker administration (propranolol) for 6 days after burn, not only reduced the number of LSKs and MafB cells in multipotent progenitors, but also influenced myelo-erythroid bifurcation by increasing the MEPs and reducing the granulocyte monocyte progenitors in the bone marrow of burn mice. Furthermore, similar results were observed in burn patients’ peripheral blood mononuclear cellderived ex vivo culture system, demonstrating that commitment stage of erythropoiesis is impaired in burn patients and intervention with propranolol (nonselective 1,2-adrenergic blocker) increases MEPs. Also, MafB cells that were significantly increased following standard burn care could be mitigated when propranolol was administered to burn patients, establishing the mechanistic regulation of erythroid commitment by myeloid regulatory transcription factor MafB. Overall, results demonstrate that -adrenergic blockers following burn injury can redirect the hematopoietic commitment toward erythroid lineage by lowering MafB expression in multipotent progenitors and be of potential therapeutic value to increase erythropoietin responsiveness in burn patients.