Indiana University-Purdue University Indianapolis (IUPUI) / Hematopoietic stem and progenitor cells (HSCs/HPCs) transplantation is a curative
treatment for a variety of hematologic and non-hematologic diseases. Successful HSC
transplantation requires infusing patients with a sufficient number of long-term engrafting
HSCs. As a result, research efforts have focused on optimizing the collection process.
Previous work established that harvesting mouse bone marrow HSCs under low oxygen
tension similar to that reported for the bone marrow niche in situ (physioxia), results in
enhanced HSC recovery and function. However, collecting bone marrow cells under
physioxia is not a clinically viable approach. Here, I demonstrated that the collection and
processing of peripheral blood mobilized with G-CSF alone or G-CSF and Plerixafor under
physioxia resulted in a greater number of phenotypically defined long-term engrafting
HSCs. Using high-resolution single cell sequencing to explore the molecular programs
governing HSCs under physioxia, I identified increased expression of genes involved in
HSC self-renewal and maintenance. In contrast, HSCs under ambient air upregulated genes
implicated in HSC differentiation, apoptosis, and inflammatory pathways. Furthermore,
wild-type HSCs under physioxia revealed a significant reduction in gene expression and
activity of the epigenetic modifier Tet2. Consequently, I evaluated the phenotyping,
engraftment potential and gene expression of preleukemic Tet2-/- bone marrow cells under
physioxia and ambient air. Unlike wild-type HSCs, Tet2-/- HSCs/HPCs were unresponsive to changes in oxygen tension. Notably, we observed similar phenotypes, functions, and
self-renewal and quiescence gene expression in wild-type HSCs under physioxia and Tet2-
/- HSCs under physioxia or ambient air. These findings imply that the preserved stemness
and enhanced engraftment of HSCs under physioxia may in part be a result of Tet2
downregulation. Understanding the mechanisms regulating wild-type and preleukemic
HSCs under physioxia will have therapeutic implications for optimizing HSC
transplantation and mitigating the growth advantage of preleukemic stem cells. / 2022-12-15
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/29848 |
| Date | 08 1900 |
| Creators | Aljoufi, Arafat |
| Contributors | Kaplan, Mark H., Zhang, Chi, Srour, Edward F., Kapur, Reuben |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
Page generated in 0.0132 seconds