Characterization of bipotential epidermal progenitors derived from human sebaceous gland: contrasting roles of c-Myc and beta-catenin.
The current belief is that the epidermal sebaceous gland (SG) is maintained by unipotent stem cells that are replenished by multipotent stem cells in the hair follicle (HF) bulge. However, sebocytes can be induced by c-Myc (Myc) activation in interfollicular epidermis (IFE), suggesting the existence of bipotential stem cells. We found that every SZ95 immortalized human sebocyte that underwent clonal growth in culture generated progeny that differentiated into both sebocytes and cells expressing involucrin and cornifin, markers of IFE and HF inner root sheath differentiation. The ability to generate involucrin positive cells was also observed in a new human sebocyte line, Seb-E6E7. SZ95 xenografts differentiated into SG and IFE but not HF. SZ95 cells that expressed involucrin had reduced Myc levels; however, this did not correlate with increased expression of the Myc repressor Blimp1, and Blimp1 expression did not distinguish cells undergoing SG, IFE, or HF differentiation in vivo. Overexpression of Myc stimulated sebocyte differentiation, whereas overexpression of beta-catenin stimulated involucrin and cornifin expression. In transgenic mice simultaneous activation of Myc and beta-catenin revealed mutual antagonism: Myc blocked ectopic HF formation and beta-catenin reduced SG differentiation. Overexpression of the Myc target gene Indian hedgehog did not promote sebocyte differentiation in culture and cyclopamine treatment, while reducing proliferation, did not block Myc induced sebocyte differentiation in vivo. Our studies provide evidence for a bipotential epidermal stem cell population in an in vitro model of human epidermal lineage selection and highlight the importance of Myc as a regulator of sebocyte differentiation.
Lo Celso
Cristina
C
Massachusetts General Hospital, Center for Regenerative Medicine, Boston, Massachusetts, USA.
Berta
Melanie A
MA
Braun
Kristin M
KM
Frye
Michaela
M
Lyle
Stephen
S
Zouboulis
Christos C
CC
Watt
Fiona M
FM
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002461:Cell Line, Transformed; D019070:Cell Lineage; D055233:Cornified Envelope Proline-Rich Proteins; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011498:Protein Precursors / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012627:Sebaceous Glands / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000378:metabolism*
D015415:Biomarkers; D055233:Cornified Envelope Proline-Rich Proteins; D053823:Hedgehog Proteins; C509246:IHH protein, human; D008565:Membrane Proteins; D011498:Protein Precursors; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D051176:beta Catenin; C087042:PRDM1 protein, human; C032253:involucrin; D000074462:Positive Regulatory Domain I-Binding Factor 1