Mesenchymal Stromal Cells Rescue Hypoxia-Induced Survival Defect in Ex Vivo Acute Myeloid Leukemia Cell Cultures
Abstract/Contents
- Abstract
- Acute myeloid leukemia (AML) is an aggressive cancer characterized by the clonal accumulation of immature blood cells. The cancer stem cell model hypothesizes that healthy hematopoietic stem cells (HSCs), which populate the entire blood compartment, acquire lesions over time and become leukemia stem cells (LSCs). These mutant cells are responsible for disease progression and act as a reservoir of cancer-forming cells following chemotherapy, causing relapse. In healthy hematopoiesis, mesenchymal stromal cells (MSCs) in the oxygen-poor bone marrow microenvironment are the niche for HSCs, providing factors to maintain and regulate self-renewal and multipotency. Current efforts seek to understand the role of the niche in aberrant hematopoiesis. While efforts to replicate human disease are aided by the in vitro study of primary AML patient sample cells (APSCs), these studies do not typically recapitulate the presence of MSCs or the hypoxic conditions of the niche. I found that hypoxia decreases APSC growth, but this defect can be rescued in a non-contact-dependent manner by co-culture of APSC with MSC or culture of APSC in MSC-conditioned media (CM). Cytokine detection analysis showed that MSC-CM contained high levels of cytokines whose transcripts are also highly expressed in primary MSCs from healthy donors. Although no singular tested cytokine was necessary for APSC survival, I determined that the expression of cytokines and receptors can independently cluster healthy and leukemic cell subsets. Therefore, cytokine combinations may contribute to APSC survival. Collectively, these results show that MSCs are sufficient to enhance APSC survival in physiologic hypoxia. The niche-like ex vivo model I established will enable the translation of laboratory findings into clinical applications.
Description
| Type of resource | text |
|---|---|
| Date modified | December 5, 2022 |
| Publication date | May 6, 2022; May 2022 |
Creators/Contributors
| Author | Martinez-Krams, Daniel |
https://orcid.org/0000-0001-9731-605X
(unverified)
|
|---|---|---|
| Thesis advisor | Majeti, Ravindra |
https://orcid.org/0000-0002-5814-0984
(unverified)
|
| Thesis advisor | Cyert, Martha |
https://orcid.org/0000-0003-3825-7437
(unverified)
|
| Degree granting institution | Stanford University, Department of Biology |
Subjects
| Subject | Biology |
|---|---|
| Subject | Acute myeloid leukemia |
| Subject | Cancer |
| Subject | Hematopoiesis |
| Subject | Microenvironment |
| Subject | Niche |
| Subject | Conditioned media |
| Subject | Cytokines |
| Subject | Personalized medicine |
| Subject | Drug discovery |
| Subject | Stem cells |
| Subject | Hypoxia |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
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- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).
Preferred citation
- Preferred citation
- Martinez-Krams, D. and Majeti, R. (2022). Mesenchymal Stromal Cells Rescue Hypoxia-Induced Survival Defect in Ex Vivo Acute Myeloid Leukemia Cell Cultures. Stanford Digital Repository. Available at https://purl.stanford.edu/yd973qj5556
Collection
Undergraduate Theses, Department of Biology, 2021-2022
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