The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion
Open accessAbstract
Although self-renewal is the central property of stem cells, the underlying mechanism remains inadequately defined. Using a hematopoietic stem and progenitor cell (HSPC)-specific conditional induction line, we generated a compound genetic model bearing both Pten deletion and β-catenin activation. These double mutant mice exhibit a novel phenotype, including expansion of phenotypic long-term hematopoietic stem cells (LT-HSCs) without extensive differentiation. Unexpectedly, constitutive activation of β-catenin alone results in apoptosis of HSCs. However, together, the Wnt/β-catenin and PTEN/PI3k/Akt pathways interact to drive phenotypic LT-HSC expansion by inducing proliferation while simultaneously inhibiting apoptosis and blocking differentiation, demonstrating the necessity of complementary cooperation between the two pathways in promoting self-renewal. Mechanistically, β-catenin activation reduces multiple differentiation-inducing transcription factors, blocking differentiation partially through up-regulation of Inhibitor of differentiation 2 ( Id2 ). In double mutants, loss of Pten enhances the HSC anti-apoptotic factor Mcl-1. All of these contribute in a complementary way to HSC self-renewal and expansion. While permanent, genetic alteration of both pathways in double mutant mice leads to expansion of phenotypic HSCs, these HSCs cannot function due to blocked differentiation. We developed a pharmacological approach to expand normal, functional HSCs in culture using factors that reversibly activate both Wnt/β-catenin and PI3K/Akt signaling simultaneously. We show for the first time that activation of either single pathway is insufficient to expand primitive HSCs, but in combination, both pathways drive self-renewal and expansion of HSCs with long-term functional capacity.
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Cited by
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Challen, G. A., Sun, D., Mayle, A., Jeong, M., Luo, M., Rodriguez, B., Mallaney, C., Celik, H., Yang, L., Xia, Z., et al. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.06.018 · Cited by 354
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Venkatraman, A., He, X. C., Thorvaldsen, J. L., Sugimura, R., Perry, J. M., Tao, F., Zhao, M., Christenson, M. K., Sanchez, R., Yu, J. Y., et al. (2013) · Nature · doi:10.1038/nature12303 · Cited by 296
Self-citationSuppression of m6A reader Ythdf2 promotes hematopoietic stem cell expansion
Li, Z., Qian, P., Shao, W., Shi, H., He, X. C., Gogol, M., Yu, Z., Wang, Y., Qi, M., Zhu, Y., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0072-0 · Cited by 257
Self-citationArai, F., Stumpf, P. S., Ikushima, Y. M., Hosokawa, K., Roch, A., Lutolf, M. P., Suda, T., & MacArthur, B. D. (2020) · Cell Systems · doi:10.1016/j.cels.2020.11.004 · Cited by 19
Metadata
- Authors
- Perry, J. M., He, X. C., Sugimura, R., Grindley, J. C., Haug, J. S., Ding, S., & Li, L.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-09-02
- Volume
- 25
- Issue
- 18
- Pages
- 1928-1942
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2132429074
- Cited by
- 188
- References
- 11
- Type
- posted content
- Language
- en
- Open access
- diamond
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- Perry, J. M., He, X. C., Sugimura, R., Grindley, J. C., Haug, J. S., Ding, S., & Li, L. (2011). Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion. Genes & Development. https://doi.org/10.1101/gad.17421911
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