Regulation of stem cell self-renewal by microRNAs
Abstract/Contents
- Abstract
- Stem cell self-renewal is dynamically regulated in response to extrinsic stimuli, but the intrinsic mechanisms that mediate the effects of these stimuli remain elusive. Emerging evidence suggests that miRNAs, an abundant class of ~22-nt small regulatory RNAs, play key roles in controlling the post-transcriptional genetic programs in stem and progenitor cells. We systematically examined miRNA expression profiles in various normal and aberrant adult tissue-specific stem and progenitor cells. Delineation of miRNAs whose expression correlated with changes in the self-renewal properties during normal development and as the result of mutant perturbations permitted the identification of miRNAs that marked stem to progenitor transition, termed SPT-miRNAs. Expression of SPT-miRNAs correlated with the exit from a self-renewing state as well as reduced self-renewal capacity in various normal and leukemia stem cells, suggesting that they may play a role in post-transcriptional gene silencing of key mediators of stem cell self-renewal. Consistent with this hypothesis, premature expression of a subset of these miRNAs could diminish the reconstitution potential of hematopoietic stem cells (HSCs) and the self-renewal of embryonic stem cells (ESCs). Furthermore, SPT-miRNAs targeted genes necessary for the self-renewal of HSCs, suggesting that up-regulation of these miRNAs permitted the efficient silencing of self-renewal programs during the stem to progenitor transition. Given the functional overlap of SPT-miRNAs in both embryonic and adult stem cells, we hypothesized that the expression of some SPT-miRNAs may be actively repressed by extrinsic signaling cues in stem cells at multiple developmental stages to potentiate their self-renewal. By subjecting ESCs to various culture conditions that diminished their self-renewal efficiency, we observed an up-regulation of a subset of SPT-miRNAs; in particular, members of the miR-181 family. Ectopic expression of this miRNA reduced ESC self-renewal whereas its deletion augmented ESC self-renewal in serum-free medium. These changes in self-renewal were attributable to simultaneous modulation of ESC proliferation and lineage commitment via target interactions with Lin28A, Spry4, and Dusp6. Finally, we found that the BMP-signaling pathway, necessary for the efficient self-renewal of ESCs, played a key role in the suppression of miR-181a. Collectively, these results reveal how extrinsic signaling cues mediate the quantitative post-transcriptional regulation of stem cell self-renewal programs via the modulation of miRNAs. Our study demonstrated one approach to identify and investigate the role of intrinsic regulators and provided novel insight into how to uncover the intrinsic regulators of stem cell self-renewal with implications on manipulation of stem cell expansion ex vivo.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2012 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Arnold, Christopher Paul |
|---|---|
| Associated with | Stanford University, Program of Immunology. |
| Primary advisor | Chen, Chang-Zheng |
| Thesis advisor | Chen, Chang-Zheng |
| Thesis advisor | Cleary, Michael L |
| Thesis advisor | Fuller, Margaret |
| Thesis advisor | Longaker, Michael T |
| Thesis advisor | Sage, Julien |
| Advisor | Cleary, Michael L |
| Advisor | Fuller, Margaret |
| Advisor | Longaker, Michael T |
| Advisor | Sage, Julien |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Christopher Paul Arnold. |
|---|---|
| Note | Submitted to the Program of Immunology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2012. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2012 by Christopher Paul Arnold
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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