Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells

Abstract

Our understanding of how mesodermal tissue is formed has been limited by the absence of specific and reliable markers of early mesoderm commitment. We report that mesoderm commitment from human embryonic stem cells (hESCs) is initiated by epithelialto-mesenchymal transition (EMT) as shown by gene expression profiling and by reciprocal changes in expression of the cell surface proteins, EpCAM/CD326 and NCAM/CD56. Molecular and functional assays reveal that the earliest CD326 − CD56 + cells, generated from hESCs in the presence of activin A, BMP4, VEGF, and FGF2, represent a multipotent mesoderm-committed progenitor population. CD326 − CD56 + progenitors are unique in their ability to generate all mesodermal lineages including hematopoietic, endothelial, mesenchymal (bone, cartilage, fat, fibroblast), smooth muscle, and cardiomyocytes, while lacking the pluripotency of hESCs. CD326 − CD56 + cells are the precursors of previously reported, more lineage-restricted mesodermal progenitors. These findings present a unique approach to study how germ layer specification is regulated and offer a promising target for tissue engineering.CD326 | CD56 | epithelial-to-mesenchymal transition | mesenchyme | hematopoiesis

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…Moreover, although NCAM is a renal developmental marker [87][88][89][90], human nephrogenesis completely ceases at 34 weeks of human gestation, excluding the potential for aberrant development caused by anti-NCAM treatment. Therefore, from a clinical standpoint, a combined regimen involving the specific eradication of the WT CICs via targeting of the NCAM molecule, might prove useful in reducing chemotherapy toxicity in all WT patients and particularly in those that do not respond to conventional treatment or those with recurrent disease.…”

MSX2 mediates entry of human pluripotent stem cells into mesendoderm by simultaneously suppressing SOX2 and activating NODAL signaling

“…We induced directed mesendoderm differentiation using a previously described protocol with some modifications [40] (Supplementary information, Figure S2A). The presence of Activin A, BMP4, Wnt3a and bFGF induced H1 hESCs to adopt a differentiation morphology (Supplementary information, Figure S2B) and increased the expression of mesendoderm markers including T, MIXL1 and others (Supplementary information, Figure S2C).…”

MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation

“…Pluripotent stem cells can be induced into ectoderm, endoderm and mesoderm, recapitulating the early events in embryogenesis 5,6 . Early differentiation involves the induction of cell line-specific transcription factors, whereas the late stages of differentiation are less well characterized 4,[7][8][9] . Alternative splicing is a means by which the genome can control the expression of different protein isoforms that can drive fundamental cellular changes and this is mostly achieved through the differential expression of RNA-binding proteins [10][11][12] .…”

“…I ntense efforts are dedicated to the study of stem cells because of the potential medical benefits and the insights into differentiation that they offer [1][2][3][4] . Pluripotent stem cells can be induced into ectoderm, endoderm and mesoderm, recapitulating the early events in embryogenesis 5,6 .…”