Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Merced Electronic Theses and Dissertations (2024)

Hematopoiesis depends on complex interactions between hematopoietic stem cells (HSCs) and the bone marrow (BM) microenvironment. However, alterations in this regulated system can lead to malignant transformation and hematopoietic diseases. Acute myeloid leukemia (AML) is characterized by uncontrolled growth of leukemic blasts in the BM and is the most common acute leukemia in adults. Tumor survival after cytotoxic treatment of AML patients remains a major therapeutic challenge, contributing to disease relapse. Fine-tuning the cytotoxic conditioning regimen to discover the most effective treatment plan has the potential to significantly improve outcomes in AML patients, thereby reducing the risk of relapse. The mechanism by which conditioning achieves therapeutic outcomes is through BM ablation. Additionally, conditioning can impact different compartments of the BM microenvironment. In this study, we investigated the impact of busulfan conditioning on the BM niche, focusing on how the intensity of cytotoxic conditioning regimens and animal age influence this dynamic process. We later expanded our findings to an AML mouse model to evaluate the BM niche around resistant tumor cells after cytotoxic therapy.

By examining the impact of varying dosages and recipient age factors on treatment response as well as BM microenvironment adjacent to the residual tumor cells after therapy, we sought to optimize chemotherapy regimens and establish the groundwork for tailoring treatment strategies to AML cancer patients.

    Cover page: Cytotoxic Conditioning-Induced Changes in Bone Marrow Microenvironment: A Study in Wild-Type and AML Mouse Models
    • Article
    • Peer Reviewed
    UC Merced Previously Published Works (2022)
    The contributions of skeletal cells to the processes of B cell development in the bone marrow (BM) have not been completely described. The von-Hippel Lindau protein (VHL) plays a key role in cellular responses to hypoxia. Previous work showed that Dmp1-Cre;Vhl conditional knockout mice (VhlcKO), which deletes Vhl in subsets of mesenchymal stem cells, late osteoblasts and osteocytes, display dysregulated bone growth and reduction in B cells. Here, we investigated the mechanisms underlying the B cell defects using flow cytometry and high-resolution imaging. In the VhlcKO BM, B cell progenitors were increased in frequency and number, whereas Hardy Fractions B-F were decreased. VhlcKO Fractions B-C cells showed increased apoptosis and quiescence. Reciprocal BM chimeras confirmed a B cell-extrinsic source of the VhlcKO B cell defects. In support of this, VhlcKO BM supernatant contained reduced CXCL12 and elevated EPO levels. Intravital and ex vivo imaging revealed VhlcKO BM blood vessels with increased diameter, volume, and a diminished blood-BM barrier. Staining of VhlcKO B cells with an intracellular hypoxic marker indicated the natural existence of distinct B cell microenvironments that differ in local oxygen tensions and that the B cell developmental defects in VhlcKO BM are not initiated by hypoxia. Our studies identify novel mechanisms linking altered bone homeostasis with drastic BM microenvironmental changes that dysregulate B cell development.
      Cover page: Deletion of Vhl in Dmp1-Expressing Cells Causes Microenvironmental Impairment of B Cell Lymphopoiesis
      • Article
      • Peer Reviewed
      UC Merced Previously Published Works (2024)
      The thymus, a key organ in the adaptive immune system, is sensitive to a variety of insults including cytotoxic preconditioning, which leads to atrophy, compression of the blood vascular system, and alterations in hemodynamics. Although the thymus has innate regenerative capabilities, the production of T cells relies on the trafficking of lymphoid progenitors from the bone marrow through the altered thymic blood vascular system. Our understanding of thymic blood vascular hemodynamics is limited due to technical challenges associated with accessing the native thymus in live mice. To overcome this challenge, we developed an intravital two-photon imaging method to visualize the native thymus in vivo and investigated functional changes to the vascular system following sublethal irradiation. We quantified blood flow velocity and shear rate in cortical blood vessels and identified a subtle but significant increase in vessel leakage and diameter ~24 hrs post-sublethal irradiation. Ex vivo whole organ imaging of optically cleared thymus lobes confirmed a disruption of the thymus vascular structure, resulting in an increase in blood vessel diameter and vessel area, and concurrent thymic atrophy. This novel two-photon intravital imaging method enables a new paradigm for directly investigating the thymic microenvironment in vivo.
        Cover page: Intravital two-photon microscopy of the native mouse thymus
        • Article
        • Peer Reviewed
        UC Merced Previously Published Works (2021)
        Conducting polymer hydrogels combine electrical conductivity and tunable water content, rendering them strong candidates for a range of applications including biosensors, cell culture platforms, and energy storage devices. However, these hydrogels are mechanically brittle and prone to damage, prohibiting their use in emerging applications involving dynamic movement and large mechanical deformation. Here, we demonstrate that applying the concept of architecture to conducting polymer hydrogels can circumvent these impediments. A stereolithography 3D printing method is developed to successfully fabricate such hydrogels in complex lattice structures. The resulting hydrogels exhibit elastic compressibility, high fracture strain, enhanced cycling stability, and damage-tolerant properties despite their chemical composition being identical to their brittle, solid counterparts. Furthermore, concentrating the deformation to the 3D geometry, rather than polymer microstructure, effectively decouples the mechanical and electrical properties of the hydrogel lattices from their intrinsic properties associated with their chemical composition. The confluence of these new physical properties for conducting polymer hydrogels opens broad opportunities for a myriad of dynamic applications.
          Cover page: 3D printed architected conducting polymer hydrogels
          Top