A developmental roadmap for the diversification of human tissue fates from pluripotent cells
Abstract/Contents
- Abstract
- One aspiration of regenerative medicine has been to produce pure populations of human tissue progenitors from differentiating pluripotent stem cells, potentially providing limitless tissues for patients-in-need. Yet, the developmental process through which pluripotent cells become diversified into a broad array of human tissue progenitors in vivo remains poorly ambiguous. Consequently in vitro stem-cell differentiation often generates an impure mixture of cell-types poorly suited for therapeutic purposes. To more accurately guide stem-cell differentiation, I have systematically mapped the pairwise lineage choices through which pluripotent cells become diversified into a broad array of derivatives belonging to the human endoderm germ layer (which gives rise to lungs, liver, pancreas, intestines and so forth) and mesoderm germ layer (which yields bone, heart and blood amongst other cell-types). At each binary lineage choice, I determined the signals that drove cells to one fate or the other. By providing the inductive signals to steer stem cells towards one lineage while inhibiting the repressive signals that instead instructed alternate fates, I could "force" pluripotent stem cells to differentiate into a pure population of a single cell-type at each lineage juncture. This approach of logically guiding stem-cell differentiation by inhibiting alternate lineage choices yielded highly pure populations of transplantable human liver progenitors, bone progenitors and heart progenitors that could each engraft in vivo in respective animal models, providing the starting point for future cell replacement therapy. Moreover by profiling transcriptional and chromatin changes between purified populations of different human endoderm and mesoderm progenitors, I defined stepwise changes in gene expression and revealed opening and closing of chromatin elements at each developmental step. Collectively, I have reconstituted aspects of human development in culture, providing a versatile platform to produce purified populations of tissue progenitors for regenerative medicine, to systematically identify the positive and negative signals that guide cell-fate choice at each lineage transition, and to understand the molecular underpinnings of human development. Akin to the relationship of biochemistry to genetics, the ability to synthetically reconstitute a process in a reductionist system demonstrates a causal understanding of how the process naturally works, and these are the goals of pluripotent stem cell differentiation as pertains to developmental biology; to artificially reconstitute complex developmental processes in a dish, to causally understand development at increasingly-higher resolution; and ultimately to achieve precise control over stem-cell differentiation to realize a new era of regenerative medicine.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2016 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Loh, Kyle M | |
|---|---|---|
| Associated with | Stanford University, Department of Developmental Biology. | |
| Primary advisor | Weissman, Irving L | |
| Thesis advisor | Weissman, Irving L | |
| Thesis advisor | Beachy, Philip Arden | |
| Thesis advisor | Fuller, Margaret | |
| Thesis advisor | Nusse, Roel, 1950- | |
| Advisor | Beachy, Philip Arden | |
| Advisor | Fuller, Margaret | |
| Advisor | Nusse, Roel, 1950- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Kyle M. Loh. |
|---|---|
| Note | Submitted to the Department of Developmental Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2016. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2016 by Kyle M. Loh
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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