title: Developmental insights from early mammalian embryos and core signaling pathways that influence human pluripotent cell growth and differentiation.
abstract: Human pluripotent stem cells (hPSCs) have two potentially attractive applications: cell replacement-based therapies and drug discovery. Both require the efficient generation of large quantities of clinical-grade stem cells that are free from harmful genomic alterations. The currently employed colony-type culture methods often result in low cell yields, unavoidably heterogeneous cell populations, and substantial chromosomal abnormalities. Here, we shed light on the structural relationship between hPSC colonies/embryoid bodies and early-stage embryos in order to optimize current culture methods based on the insights from developmental biology. We further highlight core signaling pathways that underlie multiple epithelial-to-mesenchymal transitions (EMTs), cellular heterogeneity, and chromosomal instability in hPSCs. We also analyze emerging methods such as non-colony type monolayer (NCM) and suspension culture, which provide alternative growth models for hPSC expansion and differentiation. Furthermore, based on the influence of cell-cell interactions and signaling pathways, we propose concepts, strategies, and solutions for production of clinical-grade hPSCs, stem cell precursors, and miniorganoids, which are pivotal steps needed for future clinical applications.
authors.affiliation: NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: cheng@mail.nih.gov.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Chen
authors.affiliation: NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Mallon
authors.affiliation: Information Technology and Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Hamilton
authors.affiliation: The Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Ronald D G
authors.initials: RD
authors.lastname: McKay
authors.affiliation: Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Pamela G
authors.initials: PG
authors.lastname: Robey
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D006801:Humans; D008322:Mammals / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction