Synergy between pluripotent stem cell-derived macrophages and self-renewing macrophages: Envisioning a promising avenue for the modelling and cell therapy of infectious diseases

As crucial phagocytes of the innate immune system, macrophages (M phi s) protect mammalian hosts, maintain tissue homeostasis and influence disease pathogenesis. Nonetheless, M phi s are susceptible to various pathogens, including bacteria, viruses and parasites, which cause various infectious diseases, necessitating a deeper understanding of pathogen-M phi interactions and therapeutic insights. Pluripotent stem cells (PSCs) have been efficiently differentiated into PSC-derived M phi s (PSCdM phi s) resembling primary M phi s, advancing the modelling and cell therapy of infectious diseases. However, the mass production of PSCdM phi s, which lack proliferative capacity, relies on large-scale expansions of PSCs, thereby increasing both costs and culture cycles. Notably, M phi s deficient in the MafB/c-Maf genes have been reported to re-enter the cell cycle with the stimulation of specific growth factor cocktails, turning into self-renewing M phi s (SRM phi s). This review summarizes the applications of PSCdM phi s in the modelling and cell therapy of infectious diseases and strategies for establishing SRM phi s. Most importantly, we innovatively propose that PSCs can serve as a gene editing platform to creating PSC-derived SRM phi s (termed PSRM phi s), addressing the resistance of M phi s against genetic manipulation. We discuss the challenges and possible solutions in creating PSRM phi s. In conclusion, this review provides novel insights into the development of physiologically relevant and expandable M phi models, highlighting the enormous potential of PSRM phi s as a promising avenue for the modelling and cell therapy of infectious diseases.