Browsing by Author "Trinh, Thao"

Now showing 1 - 8 of 8
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    ADGRG1 enriches for functional human hematopoietic stem cells following ex vivo expansion-induced mitochondrial oxidative stress
    (The American Society for Clinical Investigation, 2021) Chen, Yandan; Fang, Shuyi; Ding, Qingwei; Jiang, Rongzhen; He, Jiefeng; Wang, Qin; Jin, Yuting; Huang, Xinxin; Liu, Sheng; Capitano, Maegan L.; Trinh, Thao; Teng, Yincheng; Meng, Qingyou; Wan, Jun; Broxmeyer, Hal E.; Guo, Bin; BioHealth Informatics, School of Informatics and Computing
    The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1-positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34+CD133+ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.
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    Age-related decline in LEPR+ hematopoietic stem cell function
    (Springer Nature, 2023) Trinh, Thao; Ropa, James; Cooper, Scott; Aljoufi, Arafat; Sinn, Anthony; Capitano, Maegan; Broxmeyer, Hal E.; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
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    Consequences of coronavirus infections for primitive and mature hematopoietic cells: new insights and why it matters
    (Wolters Kluwer, 2021) Ropa, James; Trinh, Thao; Aljoufi, Arafat; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Purpose of review: In recent history there have been three outbreaks of betacoronavirus infections in humans, with the most recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing Coronavirus disease 2019 [COVID-19]) outbreak leading to over two million deaths, with a rapidly rising death toll. Much remains unknown about host cells and tissues affected by coronavirus infections, including the hematopoietic system. Here, we discuss the recent findings examining effects that coronavirus infection or exposure has on hematopoietic cells and the clinical implications for these effects. Recent findings: Recent studies have centered on SARS-CoV-2, demonstrating that hematopoietic stem and progenitor cells and mature immune cells may be susceptible to infection and are impacted functionally by exposure to SARS-CoV-2 Spike protein. These findings have important implications regarding hematologic complications arising from COVID-19 and other coronavirus-induced disease, which we discuss here. Summary: Infection with coronaviruses sometimes leads to hematologic complications in patients, and these hematologic complications are associated with poorer prognosis. These hematologic complications may be caused by coronavirus direct infection or impact on primitive hematopoietic cells or mature immune cells, by indirect effects on these cells, or by a combination thereof. It is important to understand how hematologic complications arise in order to seek new treatments to improve patient outcomes.
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    Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?
    (Springer Nature, 2020-11-03) Broxmeyer, Hal E.; Liu, Yan; Kapur, Reuben; Orschell, Christie M.; Aljoufi, Arafat; Ropa, James P.; Trinh, Thao; Burns, Sarah; Capitano, Maegan L.; Microbiology and Immunology, School of Medicine
    There is an ongoing shift in demographics such that older persons will outnumber young persons in the coming years, and with it age-associated tissue attrition and increased diseases and disorders. There has been increased information on the association of the aging process with dysregulation of hematopoietic stem (HSC) and progenitor (HPC) cells, and hematopoiesis. This review provides an extensive up-to date summary on the literature of aged hematopoiesis and HSCs placed in context of potential artifacts of the collection and processing procedure, that may not be totally representative of the status of HSCs in their in vivo bone marrow microenvironment, and what the implications of this are for understanding aged hematopoiesis. This review covers a number of interactive areas, many of which have not been adequately explored. There are still many unknowns and mechanistic insights to be elucidated to better understand effects of aging on the hematopoietic system, efforts that will take multidisciplinary approaches, and that could lead to means to ameliorate at least some of the dysregulation of HSCs and HPCs associated with the aging process.
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    Hypoxia Signaling Pathway in Stem Cell Regulation: Good and Evil
    (Springer Nature, 2018-06) Huang, Xinxin; Trinh, Thao; Aljoufi, Arafat; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Purpose of Review: This review summarizes the role of hypoxia and hypoxia-inducible factors (HIFs) in the regulation of stem cell biology, specifically focusing on maintenance, differentiation, and stress responses in the context of several stem cell systems. Stem cells for different lineages/tissues reside in distinct niches, and are exposed to diverse oxygen concentrations. Recent studies have revealed the importance of the hypoxia signaling pathway for stem cell functions. Recent Findings: Hypoxia and HIFs contribute to maintenance of embryonic stem cells, generation of induced pluripotent stem cells, functionality of hematopoietic stem cells, and survival of leukemia stem cells. Harvest and collection of mouse bone marrow and human cord blood cells in ambient air results in fewer hematopoietic stem cells recovered due to the phenomenon of Extra PHysiologic Oxygen Shock/Stress (EPHOSS). Summary: Oxygen is an important factor in the stem cell microenvironment. Hypoxia signaling and HIFs play important roles in modeling cellular metabolism in both stem cells and niches to regulate stem cell biology, and represent an additional dimension that allows stem cells to maintain an undifferentiated status and multilineage differentiation potential.
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    Leptin Receptor, a Surface Marker for a Subset of Highly Engrafting Long-term Functional Hematopoietic Stem Cells
    (Springer Nature, 2021) Trinh, Thao; Ropa, James; Aljoufi, Arafat; Cooper, Scott; Sinn, Anthony; Srour, Edward F.; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    The hematopoietic system is sustained by a rare population of hematopoietic stem cells (HSCs), which emerge during early embryonic development and then reside in the hypoxic niche of the adult bone marrow microenvironment. Although leptin receptor (Lepr)-expressing stromal cells are well-studied as critical regulators of murine hematopoiesis, the biological implications of Lepr expression on HSCs remain largely unexplored. We hypothesized that Lepr+HSCs are functionally different from other HSCs. Using in vitro and in vivo experimental approaches, we demonstrated that Lepr further differentiates SLAM HSCs into two distinct populations; Lepr+HSCs engrafted better than Lepr−HSCs and self-renewed more extensively as noted in secondary transplants. Molecularly, Lepr+HSCs were characterized by a proinflammatory transcriptomic profile enriched for Type-I Interferon and Interferon-gamma (IFN-γ) response pathways, which are known to be critical for the emergence of HSCs in the embryo. We conclude that although Lepr+HSCs represent a minor subset of HSCs, they are highly engrafting cells that possess embryonic-like transcriptomic characteristics, and that Lepr can serve as a reliable marker for functional long term HSCs, which may have potential clinical applicability.
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    Peripheral blood-derived mesenchymal stem cells demonstrate immunomodulatory potential for therapeutic use in horses
    (PLOS, 2019-03-14) Longhini, Ana Leda F.; Salazar, Tatiana E.; Vieira, Cristiano; Trinh, Thao; Duan, Yaqian; Pay, Louise M.; Li Calzi, Sergio; Losh, Megan; Johnston, Nancy A.; Xie, Huisheng; Kim, Minsu; Hunt, Robert J.; Yoder, Mervin C.; Santoro, Domenico; McCarrel, Taralyn M.; Grant, Maria B.; Ophthalmology, School of Medicine
    Previously, we showed that mesenchymal stem cells (MSC) can be mobilized into peripheral blood using electroacupuncture (EA) at acupoints, LI-4, LI-11, GV-14, and GV-20. The purpose of this study was to determine whether EA-mobilized MSC could be harvested and expanded in vitro to be used as an autologous cell therapy in horses. Peripheral blood mononuclear cells (PBMC) isolated from young and aged lame horses (n = 29) showed a marked enrichment for MSCs. MSC were expanded in vitro (n = 25) and administered intravenously at a dose of 50 x 106 (n = 24). Treatment resulted in significant improvement in lameness as assessed by the American Association of Equine Practitioners (AAEP) lameness scale (n = 23). MSCs exhibited immunomodulatory function by inhibition of lymphocyte proliferation and induction of IL-10. Intradermal testing showed no immediate or delayed immune reactions to MSC (1 x 106 to 1 x 104). In this study, we demonstrated an efficient, safe and reproducible method to mobilize and expand, in vitro, MSCs in sufficiently high concentrations for therapeutic administration. We confirm the immunomodulatory function of these cells in vitro. This non-pharmacological and non-surgical strategy for stem cell harvest has a broad range of biomedical applications and represents an improved clinically translatable and economical cell source for humans.
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    Role for Leptin and Leptin Receptors in Stem Cells During Health and Diseases
    (Springer, 2021) Trinh, Thao; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Hematopoietic stem cells (HSCs) give rise to all blood and immune cells in the body. These rare cells reside in the hypoxic niche of the bone marrow (BM) where they are subjected to a complex network of regulatory factors including cellular and molecular components. To sustain hematopoiesis over the lifetime of an individual, HSCs maintain distinctive metabolic programs, and in recent years nutritional factors have been increasingly recognized as critical regulators of HSC numbers and functions. Leptin (LEP), a neuroendocrine messenger, and its receptor (LEPR) are well-known for their immunomodulatory and energy balancing effects; yet, how LEP/LEPR signaling plays a role in hematopoiesis is under-appreciated. In this review, we summarize and highlight recent work that demonstrated involvement of LEP/LEPR in hematopoiesis under steady state or stress-associated situations as well as in pathological conditions such as cardiovascular diseases and malignancies. Although the field is only in its infancy, these studies suggest evidence of potential clinical applications and proof-of-principle for more in-depth future research.