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Published on: January 3, 2013
CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo
Benjamin T Spike1, Jonathan A Kelber2, Evan Booker3
1Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Abstract:
Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify CRIPTO and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a CRIPTO antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, CRIPTO treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks CRIPTO-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the CRIPTO/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers.
Insights
Researchers identified the CRIPTO/GRP78 pathway as key regulators of mammary stem cell behavior. This pathway influences stem cell self-renewal and differentiation, with implications for cancer stem cells.
Area of Science:
- Stem cell biology
- Developmental biology
- Cancer biology
Background:
- Extracellular signaling factors governing mammary stem cell behavior are largely unknown.
- Mammary stem cells are crucial for mammary gland development and regeneration.
Purpose of the Study:
- To identify extracellular signaling factors regulating mammary stem cell behavior.
- To investigate the role of CRIPTO and GRP78 in mammary stem cell function.
Main Methods:
- Isolation and culture of fetal and adult mammary epithelial cells.
- Development of a CRIPTO antagonist.
- CRIPTO treatment and GRP78 deletion experiments.
- Assessment of stem cell phenotype and mammary gland reconstitution capacity.
Main Results:
- CRIPTO and its receptor GRP78 regulate mammary stem cell behavior.
- A CRIPTO antagonist promotes differentiation and reduces self-renewal.
- CRIPTO treatment maintains stem cell phenotype and enhances reconstitution capacity.
- GRP78 expression marks CRIPTO-responsive stem cells; GRP78 deletion impairs reconstitution potential.
Conclusions:
- The CRIPTO/GRP78 pathway is a conserved regulator of fetal and adult mammary stem cell behavior ex vivo.
- This pathway has implications for understanding and potentially targeting stem-like cells in cancers.
