Takata K, Kozaki T, Lee CZW, Thion MS, Otsuka M, Lim S, Utami KH, Fidan K, Park DS, Malleret B, Chakarov S, See P, Low D, Low G, Garcia-Miralles M, Zeng R, Zhang J, Goh CC, Gul A, Hubert S, Lee B, Chen J, Low I, Shadan NB, Lum J, Wei TS, Mok E, Kawanishi S, Kitamura Y, Larbi A, Poidinger M, Renia L, Ng LG, Wolf Y, Jung S, Önder T, Newell E, Huber T, Ashihara E, Garel S, Pouladi MA, Ginhoux F.
Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies.