Human germ cell differentiation from fetal- and adult-derived induced pluripotent stem cells.
Historically, our understanding of molecular genetic aspects of human germ cell development has been limited, at least in part due to inaccessibility of early stages of human development to experimentation. However, the derivation of pluripotent stem cells may provide the necessary human genetic system to study germ cell development. In this study, we compared the potential of human induced pluripotent stem cells (iPSCs), derived from adult and fetal somatic cells to form primordial and meiotic germ cells, relative to human embryonic stem cells. We found that ∼5% of human iPSCs differentiated to primordial germ cells (PGCs) following induction with bone morphogenetic proteins. Furthermore, we observed that PGCs expressed green fluorescent protein from a germ cell-specific reporter and were enriched for the expression of endogenous germ cell-specific proteins and mRNAs. In response to the overexpression of intrinsic regulators, we also observed that iPSCs formed meiotic cells with extensive synaptonemal complexes and post-meiotic haploid cells with a similar pattern of ACROSIN staining as observed in human spermatids. These results indicate that human iPSCs derived from reprogramming of adult somatic cells can form germline cells. This system may provide a useful model for molecular genetic studies of human germline formation and pathology and a novel platform for clinical studies and potential therapeutical applications.
Department of Obstetrics and Gynecology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford University, Palo Alto, CA 94305, USA.
Sarita
S
Panula
Jose V
JV
Medrano
Kehkooi
K
Kee
Rosita
R
Bergström
Ha Nam
HN
Nguyen
Blake
B
Byers
Kitchener D
KD
Wilson
Joseph C
JC
Wu
Carlos
C
Simon
Outi
O
Hovatta
Renee A
RA
Reijo Pera
D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism; D006238:Haploidy; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013573:Synaptonemal Complex / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C498288:DDX4 protein, human; D053487:DEAD-box RNA Helicases