Supplementation‐dependent differences in the rates of embryonic stem cell self‐renewal, differentiation, and apoptosis
- 24 September 2003
- journal article
- research article
- Published by Wiley in Biotechnology & Bioengineering
- Vol. 84 (5), 505-517
- https://doi.org/10.1002/bit.10799
Abstract
Although it is known that leukemia inhibitory factor (LIF) supports the derivation and expansion of murine embryonic stem (ES) cells, it is unclear whether this is due to inhibitory effects of LIF on ES cell differentiation or stimulatory effects on ES cell survival and proliferation. Using an ES cell line transgenic for green fluorescent protein (GFP) expression under control of the Oct4 promoter, we were able to simultaneously track the responses of live Oct4‐GFP‐positive (ES) and ‐negative (differentiated) fractions to LIF, serum, and other growth factors. Our findings show that, in addition to inhibiting differentiation of undifferentiated cells, the administration of LIF resulted in a distinct dose‐dependent survival and proliferation advantage, thus enabling the long‐term propagation of undifferentiated cells. Competitive responses from the differentiated cell fraction could only be elicited upon addition of serum, fibroblast growth factor‐4 (FGF‐4), or insulin‐like growth factor‐1 (IGF‐1). The growth factors did not induce additional differentiation of ES cells, but rather they significantly improved the proliferation of already differentiated cells. Our analyses show that, by adjusting culture conditions, including the type and amount of growth factors or cytokines present, the frequency of media exchange, and the presence or absence of serum, we could selectively and specifically alter the survival, proliferation, and differentiation dynamics of the two subpopulations, and thus effectively control population outputs. Our findings therefore have important applications in engineering stem cell culture systems to predictably generate desired stem cells or their derivatives for various regenerative therapies. © 2003 Wiley Periodicals, Inc. Biotechnol Bioeng84: 505–517, 2003.Keywords
This publication has 56 references indexed in Scilit:
- The Ribosomal S6 Kinases, cAMP-responsive Element-binding, and STAT3 Proteins Are Regulated by Different Leukemia Inhibitory Factor Signaling Pathways in Mouse Embryonic Stem CellsJournal of Biological Chemistry, 2001
- Role of suppressors of cytokine signaling (Socs) in leukemia inhibitory factor (LIF) -dependent embryonic stem cell survivalThe FASEB Journal, 2000
- Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiationOncogene, 2000
- Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptorsOncogene, 2000
- Embryonic Stem Cell Lines Derived from Human BlastocystsScience, 1998
- Insulin-like Growth Factor 1 Inhibits Apoptosis Using the Phosphatidylinositol 3′-Kinase and Mitogen-activated Protein Kinase PathwaysJournal of Biological Chemistry, 1997
- Two Signals Are Necessary for Cell Proliferation Induced by a Cytokine Receptor gp130: Involvement of STAT3 in Anti-ApoptosisImmunity, 1996
- Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.Proceedings of the National Academy of Sciences, 1993
- Expression pattern of the mouse T gene and its role in mesoderm formationNature, 1990
- Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cellsNature, 1988