IU Indianapolis ScholarWorks :: Browsing by Author "Liu, Jianyun"

Browsing by Author "Liu, Jianyun"

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Bone marrow- or adipose-mesenchymal stromal cell secretome preserves myocardial transcriptome profile and ameliorates cardiac damage following ex vivo cold storage
(Elsevier, 2022) Scott, Susan R.; March, Keith L.; Wang, I-Wen; Singh, Kanhaiya; Liu, Jianyun; Turrentin, Mark; Sen, Chandan K.; Wang, Meijing; Surgery, School of Medicine
Background: Heart transplantation, a life-saving approach for patients with end-stage heart disease, is limited by shortage of donor organs. While prolonged storage provides more organs, it increases the extent of ischemia. Therefore, we seek to understand molecular mechanisms underlying pathophysiological changes of donor hearts during prolonged storage. Additionally, considering mesenchymal stromal cell (MSC)-derived paracrine protection, we aim to test if MSC secretome preserves myocardial transcriptome profile and whether MSC secretome from a certain source provides the optimal protection in donor hearts during cold storage. Methods and results: Isolated mouse hearts were divided into: no cold storage (control), 6 h cold storage (6 h-I), 6 h-I + conditioned media from bone marrow MSCs (BM-MSC CM), and 6 h-I + adipose-MSC CM (Ad-MSC CM). Deep RNA sequencing analysis revealed that compared to control, 6 h-I led to 266 differentially expressed genes, many of which were implicated in modulating mitochondrial performance, oxidative stress response, myocardial function, and apoptosis. BM-MSC CM and Ad-MSC CM restored these gene expression towards control. They also improved 6 h-I-induced myocardial functional depression, reduced inflammatory cytokine production, decreased apoptosis, and reduced myocardial H2O2. However, neither MSC-exosomes nor exosome-depleted CM recapitulated MSC CM-ameliorated apoptosis and CM-improved mitochondrial preservation during cold ischemia. Knockdown of Per2 by specific siRNA abolished MSC CM-mediated these protective effects in cardiomyocytes following 6 h cold storage. Conclusions: Our results demonstrated that using MSC secretome (BM-MSCs and Ad-MSCs) during prolonged cold storage confers preservation of the normal transcriptional "fingerprint", and reduces donor heart damage. MSC-released soluble factors and exosomes may synergistically act for donor heart protection.
Cellular components of the hematopoietic niche and their regulation of hematopoietic stem cell function
(Wolters Kluwer, 2021) Ghosh, Joydeep; El Koussa, Roy; Mohamad, Safa F.; Liu, Jianyun; Kacena, Melissa A.; Srour, Edward F.; Medicine, School of Medicine
Purpose of review: Development and functions of hematopoietic stem cells (HSC) are regulated by multiple cellular components of the hematopoietic niche. Here we review the recent advances in studying the role of three such components -- osteoblasts, osteomacs, and megakaryocytes and how they interact with each other in the hematopoietic niche to regulate HSC. Recent findings: Recent advances in transgenic mice models, scRNA-seq, transcriptome profile, proteomics, and live animal imaging have revealed the location of HSC within the bone and signaling molecules required for the maintenance of the niche. Interaction between megakaryocytes, osteoblasts and osteomacs enhances hematopoietic stem and progenitor cells (HSPC) function. Studies also revealed the niche as a dynamic entity that undergoes cellular and molecular changes in response to stress. Aging, which results in reduced HSC function, is associated with a decrease in endosteal niches and osteomacs as well as reduced HSC--megakaryocyte interactions. Summary: Novel approaches to study the cellular components of the niche and their interactions to regulate HSC development and functions provided key insights about molecules involved in the maintenance of the hematopoietic system. Furthermore, these studies began to build a more comprehensive model of cellular interactions and dynamics in the hematopoietic niche.
Chondroitin sulfate supplementation improves clinical outcomes in a murine model of necrotizing enterocolitis
(Wiley, 2023) Manohar, Krishna; Hosfield, Brian D.; Mesfin, Fikir M.; Colgate, Cameron; Shelley, William Christopher; Liu, Jianyun; Zeng, Lifan; Brokaw, John P.; Markel, Troy A.; Surgery, School of Medicine
Necrotizing enterocolitis (NEC) continues to be a devastating disease in preterm neonates and has a paucity of medical management options. Chondroitin sulfate (CS) is a naturally occurring glycosaminoglycan (GAG) in human breast milk (HM) and has been shown to reduce inflammation. We hypothesized that supplementation with CS in an experimental NEC model would alter microbial diversity, favorably alter the cytokine profile, and (like other sulfur compounds) improve outcomes in experimental NEC via the eNOS pathway. NEC was induced in 5-day-old pups. Six groups were studied (n = 9-15/group): (1) WT breastfed and (2) Formula fed controls, (3) WT NEC, (4) WT NEC + CS, (5) eNOS KO (knockout) NEC, and (6) eNOS KO NEC + CS. Pups were monitored for clinical sickness score and weights. On postnatal day 9, the pups were killed. Stool was collected from rectum and microbiome analysis was done with 16 s rRNA sequencing. Intestinal segments were examined histologically using a well-established injury scoring system and segments were homogenized and analyzed for cytokine profile. Data were analyzed using GraphPad Prism with p < 0.05 considered significant. CS supplementation in formula improved experimental NEC outcomes when compared to NEC alone. CS supplementation resulted in similar improvement in NEC in both the WT and eNOS KO mice. CS supplementation did not result in microbial changes when compared to NEC alone. Our data suggest that although CS supplementation improved outcomes in NEC, this protection is not conferred via the eNOS pathway or alteration of microbial diversity. CS therapy in NEC does improve the intestinal cytokine profile and further experiments will explore the mechanistic role of CS in altering immune pathways in this disease.
Forming a Complex with MHC Class I Molecules Interferes with Mouse CD1d Functional Expression
(Public Library of Science, 2013-08-29) Gourapura, Renukaradhya J.; Khan, Masood A.; Gallo, Richard M.; Shaji, Daniel; Liu, Jianyun; Brutkiewicz, Randy R.; Microbiology and Immunology, School of Medicine
CD1d molecules are structurally similar to MHC class I, but present lipid antigens as opposed to peptides. Here, we show that MHC class I molecules physically associate with (and regulate the functional expression of) mouse CD1d on the surface of cells. Low pH (3.0) acid stripping of MHC class I molecules resulted in increased surface expression of murine CD1d on antigen presenting cells as well as augmented CD1d-mediated antigen presentation to NKT cells. Consistent with the above results, TAP1-/- mice were found to have a higher percentage of type I NKT cells as compared to wild type mice. Moreover, bone marrow-derived dendritic cells from TAP1-/- mice showed increased antigen presentation by CD1d compared to wild type mice. Together, these results suggest that MHC class I molecules can regulate NKT cell function, in part, by masking CD1d.
Genetic engineering of porcine endothelial cell lines for evaluation of human-to-pig xenoreactive immune responses
(Springer Nature, 2021-06-23) Li, Ping; Walsh, Julia R.; Lopez, Kevin; Isidan, Abdulkadir; Zhang, Wenjun; Chen, Angela M.; Goggins, William C.; Higgins, Nancy G.; Liu, Jianyun; Brutkiewicz, Randy R.; Smith, Lester J.; Hara, Hidetaka; Cooper, David K.C.; Ekser, Burcin; Surgery, School of Medicine
Xenotransplantation (cross-species transplantation) using genetically-engineered pig organs offers a potential solution to address persistent organ shortage. Current evaluation of porcine genetic modifications is to monitor the nonhuman primate immune response and survival after pig organ xenotransplantation. This measure is an essential step before clinical xenotransplantation trials, but it is time-consuming, costly, and inefficient with many variables. We developed an efficient approach to quickly examine human-to-pig xeno-immune responses in vitro. A porcine endothelial cell was characterized and immortalized for genetic modification. Five genes including GGTA1, CMAH, β4galNT2, SLA-I α chain, and β2-microglobulin that are responsible for the production of major xenoantigens (αGal, Neu5Gc, Sda, and SLA-I) were sequentially disrupted in immortalized porcine endothelial cells using CRISPR/Cas9 technology. The elimination of αGal, Neu5Gc, Sda, and SLA-I dramatically reduced the antigenicity of the porcine cells, though the cells still retained their ability to provoke human natural killer cell activation. In summary, evaluation of human immune responses to genetically modified porcine cells in vitro provides an efficient method to identify ideal combinations of genetic modifications for improving pig-to-human compatibility, which should accelerate the application of xenotransplantation to humans.
Gut-Brain cross talk: The pathogenesis of neurodevelopmental impairment in necrotizing enterocolitis
(Frontiers Media, 2023-02-15) Manohar, Krishna; Mesfin, Fikir M.; Liu, Jianyun; Shelley, W. Christopher; Brokaw, John P.; Markel, Troy A.; Surgery, School of Medicine
Necrotizing enterocolitis (NEC) is a devastating condition of multi-factorial origin that affects the intestine of premature infants and results in high morbidity and mortality. Infants that survive contend with several long-term sequelae including neurodevelopmental impairment (NDI)-which encompasses cognitive and psychosocial deficits as well as motor, vision, and hearing impairment. Alterations in the gut-brain axis (GBA) homeostasis have been implicated in the pathogenesis of NEC and the development of NDI. The crosstalk along the GBA suggests that microbial dysbiosis and subsequent bowel injury can initiate systemic inflammation which is followed by pathogenic signaling cascades with multiple pathways that ultimately lead to the brain. These signals reach the brain and activate an inflammatory cascade in the brain resulting in white matter injury, impaired myelination, delayed head growth, and eventual downstream NDI. The purpose of this review is to summarize the NDI seen in NEC, discuss what is known about the GBA, explore the relationship between the GBA and perinatal brain injury in the setting of NEC, and finally, highlight the existing research into possible therapies to help prevent these deleterious outcomes.
Hydrogen Sulfide Improves Outcomes in a Murine Model of Necrotizing Enterocolitis via the Cys440 Residue on Endothelial Nitric Oxide Synthase
(Elsevier, 2023) Hunter, Chelsea E.; Mesfin, Fikir M.; Manohar, Krishna; Liu, Jianyun; Shelley, W. Christopher; Brokaw, John P.; Pecoraro, Anthony R.; Hosfield, Brian D.; Markel, Troy A.; Surgery, School of Medicine
Background: Hydrogen sulfide (H2S) has been shown to improve outcomes in a murine model of necrotizing enterocolitis (NEC). There is evidence in humans that H2S relies on endothelial nitric oxide synthase (eNOS) to exert its protective effects, potentially through the persulfidation of eNOS at the Cysteine 443 residue. We obtained a novel mouse strain with a mutation at this residue (eNOSC440G) and hypothesized that this locus would be critical for GYY4137 (an H2S donor) to exert its protective effects. Methods: Necrotizing enterocolitis was induced in 5-day old wild type (WT) and eNOSC440G mice using intermittent exposure to hypoxia and hypothermia in addition to gavage formula feeds. On postnatal day 9, mice were humanely euthanized. Data collected included daily weights, clinical sickness scores, histologic lung injury, intestinal injury (macroscopically and histologically), and intestinal perfusion. During the NEC model, pups received daily intraperitoneal injections of either GYY4137 (50 mg/kg) or PBS (vehicle). Data were tested for normality and compared using t-test or Mann-Whitney, and a p-value <0.05 was considered significant. Results: In WT mice, the administration of GYY4137 significantly improved clinical sickness scores, attenuated intestinal and lung injury, and improved mesenteric perfusion compared to vehicle (p < 0.05). In eNOSC440G mice, the treatment and vehicle groups had similar clinical sickness scores, intestinal and lung injury scores, and intestinal perfusion. Conclusions: GYY4137 administration improves clinical outcomes, attenuates intestinal and lung injury, and improves perfusion in a murine model of necrotizing enterocolitis. The beneficial effects of GYY4137 are dependent on the Cys440 residue of eNOS.
Immune evasion of the CD1d/NKT cell axis
(Elsevier, 2018-06) Brutkiewicz, Randy R.; Yunes-Medina, Laura; Liu, Jianyun; Microbiology and Immunology, School of Medicine
Many reviews on the CD1d/NKT cell axis focus on the ability of CD1d-restricted NKT cells to serve as effector cells in a variety of disorders, be they infectious diseases, cancer or autoimmunity. In contrast, here, we discuss the ways that viruses, bacteria and tumor cells can evade the CD1d/NKT cell axis. As a result, these disease states have a better chance to establish a foothold and potentially cause problems for the subsequent adaptive immune response, as the host tries to rid itself of infections or tumors.
Importance of Per2 in cardiac mitochondrial protection during stress
(Springer Nature, 2024-01-14) Bhaskara, Meghana; Anjorin, Olufisayo; Yoniles, Arris; Liu, Jianyun; Wang, Meijing; Surgery, School of Medicine
During myocardial injury, inflammatory mediators and oxidative stress significantly increase to impair cardiac mitochondria. Emerging evidence has highlighted interplays between circadian protein-period 2 (Per2) and mitochondrial metabolism. However, besides circadian rhythm regulation, the direct role of Per2 in mitochondrial performance particularly following acute stress, remains unknown. In this study, we aim to determine the importance of Per2 protein's regulatory role in mitochondrial function following exposure to inflammatory cytokine TNFα and oxidative stressor H2O2 in human cardiomyocytes. Global warm ischemia (37 °C) significantly impaired complex I activity with concurrently reduced mitochondrial Per2 in adult mouse hearts. TNFα or H2O2 decreased Per2 protein levels and damaged mitochondrial respiratory function in adult mouse cardiomyocytes. Next, mitochondrial membrane potential ([Formula: see text] M) using JC-1 fluorescence probe and mitochondrial respiration capacity via Seahorse Cell Mito Stress Test were then detected in Per2 or control siRNA transfected AC16 Human Cardiomyocytes (HCM) that were subjected to 2 h-treatment of TNFα (100 ng/ml) or H2O2 (100 μM). After 4 h-treatment, cell death was also measured using Annexin V and propidium iodide apoptosis kit through flow cytometry. We found that knockdown of Per2 enhanced TNFα-induced cell death and TNFα- or H2O2-disrupted [Formula: see text]M, as well as TNFα- or H2O2-impaired mitochondrial respiration function. In conclusion, Per2 knockdown increases likelihood of cell death and mitochondrial dysfunction in human cardiomyocytes exposed to either TNFα or H2O2, supporting the protective role of Per2 in HCM during stress with a focus on mitochondrial function.
JNK2 modulates the CD1d-dependent and -independent activation of iNKT cells
(Wiley, 2019-02) Liu, Jianyun; Gallo, Richard M.; Khan, Masood A.; Iyer, Abhirami K.; Kratzke, Ian M.; Brutkiewicz, Randy R.; Microbiology and Immunology, School of Medicine
Invariant Natural Killer T (iNKT) cells play critical roles in autoimmune, anti-tumor and anti-microbial immune responses, and are activated by glycolipids presented by the MHC class I-like molecule, CD1d. How the activation of signaling pathways impacts antigen (Ag)-dependent iNKT cell activation is not well-known. In the current study, we found that the MAPK JNK2 not only negatively regulates CD1d-mediated Ag presentation in APCs, but also contributes to CD1d-independent iNKT cell activation. A deficiency in the JNK2 (but not JNK1) isoform enhanced Ag presentation by CD1d. Using a vaccinia virus (VV) infection model known to cause a loss in iNKT cells in a CD1d-independent, but IL-12-dependent manner, we found the virus-induced loss of iNKT cells in JNK2 KO mice was substantially lower than that observed in JNK1 KO or wildtype (WT) mice. Importantly, compared to WT mice, JNK2 KO mouse iNKT cells were found to express less surface IL-12 receptors. As with a VV infection, an IL-12 injection also resulted in a smaller decrease in JNK2 KO iNKT cells as compared to WT mice. Overall, our work strongly suggests JNK2 is a negative regulator of CD1d-mediated Ag presentation and contributes to IL-12-induced iNKT cell activation and loss during viral infections.

Browsing by Author "Liu, Jianyun"

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