MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages.
In metazoan organisms, terminal differentiation is generally tightly linked to cell cycle exit, whereas the undifferentiated state of pluripotent stem cells is associated with unlimited self-renewal. Here, we report that combined deficiency for the transcription factors MafB and c-Maf enables extended expansion of mature monocytes and macrophages in culture without loss of differentiated phenotype and function. Upon transplantation, the expanded cells are nontumorigenic and contribute to functional macrophage populations in vivo. Small hairpin RNA inactivation shows that continuous proliferation of MafB/c-Maf deficient macrophages requires concomitant up-regulation of two pluripotent stem cell-inducing factors, KLF4 and c-Myc. Our results indicate that MafB/c-MafB deficiency renders self-renewal compatible with terminal differentiation. It thus appears possible to amplify functional differentiated cells without malignant transformation or stem cell intermediates.
Aziz
Athar
A
Centre d'Immunologie de Marseille-Luminy (CIML), Université Aix-Marseille, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France.
Soucie
Erinn
E
Sarrazin
Sandrine
S
Sieweke
Michael H
MH
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D051258:MafB Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology; D010587:Phagocytosis; D051257:Proto-Oncogene Proteins c-maf / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation
C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C495608:Maf protein, mouse; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; C489428:Myc protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D016271:Proto-Oncogene Proteins c-myc; D016173:Macrophage Colony-Stimulating Factor