title: Myelo-erythroid commitment after burn injury is under β-adrenergic control via MafB regulation.
abstract: 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 β-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 (linnegSca1+cKit+), that the myeloid shift is accompanied with a significant reduction in megakaryocyte erythrocyte progenitors (MEPs). β-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 cell-derived ex vivo culture system, demonstrating that commitment stage of erythropoiesis is impaired in burn patients and intervention with propranolol (nonselective β1,2-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 β-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.
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Shirin
authors.initials: S
authors.lastname: Hasan
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Johnson
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mosier
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Ravi
authors.initials: R
authors.lastname: Shankar
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Peggie
authors.initials: P
authors.lastname: Conrad
authors.affiliation: Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Andrea
authors.initials: A
authors.lastname: Szilagyi
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.affiliation: Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois; and kmuthu@luc.edu.|Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois.
authors.forename: Kuzhali
authors.initials: K
authors.lastname: Muthumalaiappan
mesh_terms: D000328:Adult; D000818:Animals; D002056:Burns / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D060833:Cellular Microenvironment; D004912:Erythrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051258:MafB Transcription Factor / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D011943:Receptors, Adrenergic, beta
keywords: LSK cells; MafB; anemia; burns; catecholamine; erythro-myeloid; erythropoiesis; granulocyte monocyte progenitors; megakaryocyte erythrocyte progenitors; propranolol