TY - JOUR
T1 - PU.1 and C/EBPα/β convert fibroblasts into macrophage-like cells
AU - Feng, Ru
AU - Desbordes, Sabrina C.
AU - Xie, Huafeng
AU - Tillo, Ester Sanchez
AU - Pixley, Fiona
AU - Stanley, E. Richard
AU - Graf, Thomas
PY - 2008/4/22
Y1 - 2008/4/22
N2 - Earlier work has shown that the transcription factor C/EBPα induced a transdifferentiation of committed lymphoid precursors into macrophages in a process requiring endogenous PU.1. Here we have examined the effects of PU.1 and C/EBPα on fibroblasts, a cell type distantly related to blood cells and akin to myoblasts, adipocytes, osteoblasts, and chondroblasts. The combination of the two factors, as well as PU.1 and C/EBPβ, induced the upregulation of macrophage/hematopoietic cell surface markers in a large proportion of NIH 3T3 cells. They also up-regulated these markers in mouse embryo- and adult skin-derived fibroblasts. Based on cell morphology, activation of macrophage-associated genes, and extinction of fibroblast-associated genes, cell lines containing an attenuated form of PU.1 and C/EBPα acquired a macrophage-like phenotype. The lines also display macrophage functions: They phagocytose small particles and bacteria, mount a partial inflammatory response, and exhibit strict CSF-1 dependence for growth. The myeloid conversion is primarily induced by PU.1, with C/EBPα acting as a modulator of macrophage-specific gene expression. Our data suggest that it might become possible to induce the transdifferentiation of skin-derived fibroblasts into cell types desirable for tissue regeneration.
AB - Earlier work has shown that the transcription factor C/EBPα induced a transdifferentiation of committed lymphoid precursors into macrophages in a process requiring endogenous PU.1. Here we have examined the effects of PU.1 and C/EBPα on fibroblasts, a cell type distantly related to blood cells and akin to myoblasts, adipocytes, osteoblasts, and chondroblasts. The combination of the two factors, as well as PU.1 and C/EBPβ, induced the upregulation of macrophage/hematopoietic cell surface markers in a large proportion of NIH 3T3 cells. They also up-regulated these markers in mouse embryo- and adult skin-derived fibroblasts. Based on cell morphology, activation of macrophage-associated genes, and extinction of fibroblast-associated genes, cell lines containing an attenuated form of PU.1 and C/EBPα acquired a macrophage-like phenotype. The lines also display macrophage functions: They phagocytose small particles and bacteria, mount a partial inflammatory response, and exhibit strict CSF-1 dependence for growth. The myeloid conversion is primarily induced by PU.1, with C/EBPα acting as a modulator of macrophage-specific gene expression. Our data suggest that it might become possible to induce the transdifferentiation of skin-derived fibroblasts into cell types desirable for tissue regeneration.
KW - Cell reprogramming
KW - Differentiation plasticity
KW - Hematopoiesis
UR - http://www.scopus.com/inward/record.url?scp=43149115856&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43149115856&partnerID=8YFLogxK
U2 - 10.1073/pnas.0711961105
DO - 10.1073/pnas.0711961105
M3 - Article
C2 - 18424555
AN - SCOPUS:43149115856
SN - 0027-8424
VL - 105
SP - 6057
EP - 6062
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -