title: Engineering integrin signaling for promoting embryonic stem cell self-renewal in a precisely defined niche.
abstract: We present development and use of a 3D synthetic extracellular matrix (ECM) analog with integrin-specific adhesion ligands to characterize the microenvironmental influences in embryonic stem cell (ESC) self-renewal. Transcriptional analysis of 24 integrin subunits followed by confirmation at the translational and functional levels suggested that integrins alpha(5)beta(1), alpha(v)beta(5), alpha(6)beta(1) and alpha(9)beta(1) play important roles in maintenance of stemness in undifferentiated mouse ESCs. Using the well-defined matrix as a tool to activate integrins alpha(5)beta(1) plus alpha(v)beta(5), alpha(6)beta(1) and alpha(9)beta(1), individually and in combination, differential integrin activation was demonstrated to exert exquisite control over ESC fate decisions. Simultaneous ligation of these four integrin heterodimers promoted self-renewal, as evidence by prolonged SSEA-1, Oct4 and Nanog expression, and induced Akt1 kinase signaling along with translational regulation of other stemness-related genes. The biofunctional network we have designed based on this knowledge may be useful as a defined niche for regulating ESC pluripotency through selective cell-matrix interactions, and the method we present may be more generally useful for probing matrix interactions in stem cell self-renewal and differentiation.
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Lee
authors.forename: Jung Im
authors.initials: JI
authors.lastname: Yun
authors.forename: Yun Suk
authors.initials: YS
authors.lastname: Jo
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mochizuki
authors.forename: André J
authors.initials: AJ
authors.lastname: van der Vlies
authors.forename: Stephan
authors.initials: S
authors.lastname: Kontos
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Ihm
authors.forename: Jeong M
authors.initials: JM
authors.lastname: Lim
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry; D002450:Cell Communication / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism*; D024861:Genetic Enhancement / Q000379:methods*; D020100:Hydrogels / Q000737:chemistry / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008422:Materials Testing; D051379:Mice; D015202:Protein Engineering / Q000379:methods*; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D020100:Hydrogels; D016023:Integrins