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a The Institute for Cell Engineering,
b Departments of Gynecology & Obstetrics and
c Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Key Words. Human embryonic stem cells • Embryonic stem cell biology • Self-renewal • Stem cell differentiation • Cellular proliferation • Wnt signaling • ß-Catenin signaling • Colony formation assays
Correspondence: Linzhao Cheng, Ph.D., Stem Cell Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Broadway Research Building, Room 747, 733 N. Broadway, Baltimore, MD 21205, USA. Telephone: 410-614-6958; Fax: 443-287-5611; e-mail: lcheng{at}welch.jhu.edu
We used a panel of human and mouse fibroblasts with various abilities for supporting the prolonged growth of human embryonic stem cells (hESCs) to elucidate growth factors required for hESC survival, proliferation, and maintenance of the undifferentiated and pluripotent state (self-renewal). We found that supportive feeder cells secrete growth factors required for both hESC survival/proliferation and blocking hESC spontaneous differentiation to achieve self-renewal. The antidifferentiation soluble factor is neither leukemia inhibitory factor nor Wnt, based on blocking experiments using their antagonists. Because Wnt/ß-catenin signaling has been implicated in cell-fate determination and stem cell expansion, we further examined the effects of blocking or adding recombinant Wnt proteins on undifferentiated hESCs. In the absence of feeder cell–derived factors, hESCs cultured under a feeder-free condition survived/proliferated poorly and gradually differentiated. Adding recombinant Wnt3a stimulated hESC proliferation but also differentiation. After 4–5 days of Wnt3a treatment, hESCs that survived maintained the undifferentiated phenotype but few could form undifferentiated hESC colonies subsequently. Using a functional reporter assay, we found that the ß-catenin–mediated transcriptional activation in the canonical Wnt pathway was minimal in undifferentiated hESCs, but greatly upregulated during differentiation induced by the Wnt treatment and several other methods. Thus, Wnt/ß-catenin activation does not suffice to maintain the undifferentiated and pluripotent state of hESCs. We propose a new model for the role of Wnt/ß-catenin signaling in undifferentiated hESCs.
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