Publications by authors named "Simon Liang"

20 Publications

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Functional MRI evaluation of the effect of carotid artery stenting: a case study demonstrating cognitive improvement.

Acta Radiol Open 2021 Feb 10;10(2):2058460120988822. Epub 2021 Feb 10.

Health Sciences and Innovation, Surrey Memorial Hospital, Fraser Health Authority, British Columbia, Canada.

Background: The narrowing of the carotid arteries with plaque formation represents a major risk factor for ischemic stroke and cognitive impairments. Carotid angioplasty and stenting is a standard clinical treatment to reduce stroke risk. The cognitive effect of carotid angioplasty and stenting remains largely unknown.

Purpose: This study aims to provide direct evidence of possible effects of carotid angioplasty and stenting on cognition, using task-phase functional magnetic resonance imaging.

Material And Methods: This study received harmonized institutional ethics board approval (Grant number REB ID =H18-02495/FHREB 2018-058). Two patients had MRI scans pre-carotid angioplasty and stenting and two-month post-carotid angioplasty and stenting. Case 1 had severe (>95%) flow-limiting stenosis in the right carotid artery. Case 2 had 70% non-flow limiting stenosis in the left carotid artery. At each scan, patients completed two functional magnetic resonance imaging sessions while performing a working memory task. Accuracy, reaction time, and brain activation were analyzed for each patient for possible pre-post carotid angioplasty and stenting changes.

Results: Case 1 showed increased activation in the right (treated-side) frontal and temporal lobes post-carotid angioplasty and stenting; associated with improvements in accuracy (from 58% to 74%) and task completion rate (from 17% to 72%). Case 2 completed the tasks pre- and post-carotid angioplasty and stenting with >90% accuracy, while decreased functional magnetic resonance imaging activation in the contralateral (untreated) hemisphere and mildly increased activation in the left (treated -side) anterior circulation territory were observed post-carotid angioplasty and stenting.

Conclusion: These cases provided the first task-phase functional magnetic resonance imaging data demonstrating that carotid angioplasty and stenting improved cognitive function in the re-perfused vascular territory. The finding supports the role of carotid angioplasty and stenting in improving cognitive performance beyond reducing stroke risk.
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http://dx.doi.org/10.1177/2058460120988822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878956PMC
February 2021

SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms.

Sci Rep 2021 Jan 14;11(1):1399. Epub 2021 Jan 14.

Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.
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http://dx.doi.org/10.1038/s41598-021-80999-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809281PMC
January 2021

Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor.

Science 2019 07;365(6449):162-168

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Chimeric antigen receptor-T cell (CAR-T) therapy has been effective in the treatment of hematologic malignancies, but it has shown limited efficacy against solid tumors. Here we demonstrate an approach to enhancing CAR-T function in solid tumors by directly vaccine-boosting donor cells through their chimeric receptor in vivo. We designed amphiphile CAR-T ligands (amph-ligands) that, upon injection, trafficked to lymph nodes and decorated the surfaces of antigen-presenting cells, thereby priming CAR-Ts in the native lymph node microenvironment. Amph-ligand boosting triggered massive CAR-T expansion, increased donor cell polyfunctionality, and enhanced antitumor efficacy in multiple immunocompetent mouse tumor models. We demonstrate two approaches to generalizing this strategy to any chimeric antigen receptor, enabling this simple non-human leukocyte antigen-restricted approach to enhanced CAR-T functionality to be applied to existing CAR-T designs.
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http://dx.doi.org/10.1126/science.aav8692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800571PMC
July 2019

Differentiation of CD45‑/CD31+ lung side population cells into endothelial and smooth muscle cells in vitro.

Int J Mol Med 2019 Mar 8;43(3):1128-1138. Epub 2019 Jan 8.

Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China.

Side population (SP) cells are a small subpopulation of cells found in many mammalian tissues and organs, identified by their capacity to efflux Hoechst 33342 dye. They are enriched for stem/progenitor cell activity. SP cells isolated from the adult mouse lung can be separated into a CD45+ subset (bone marrow‑derived) and a CD45‑ subset that can be subdivided into CD31‑ and CD31+ subpopulations. CD45‑/CD31‑ lung SP (LSP) cells are known to be mesenchymal stem cells. However, CD45‑/CD31+ LSP cells are not fully characterized. In the present study, it was found that CD45‑/CD31+ LSP cells were able to form colonies. Based on the expression of vascular endothelial growth factor receptor 2 (VEGFR2), these cells were separated into VEGFR2‑ and VEGFR2+ cells. The CD45‑/CD31+/VEGFR2‑ LSP cells expressed genes characteristic of smooth muscle and endothelial progenitors, and were able to differentiate into smooth muscle and endothelial cells in vitro. The CD45‑/CD31+/VEGFR2+ LSP cells expressed genes characteristic of endothelial progenitors and gave rise to endothelial cells, although not smooth muscle, in vitro. The data demonstrate that CD45‑/CD31+/VEGFR2‑ LSP cells differentiated into CD45‑/CD31+/VEGFR2+ LSP cells and then endothelial cells, indicating that CD45‑/CD31+/VEGFR2+ LSP cells are likely to be derived from CD45‑/CD31+/VEGFR2‑ LSP cells. Taken together, the results suggest that CD45‑/CD31+ LSP cells can be separated into CD45‑/CD31+/VEGFR2‑ LSP cells, which may be progenitors of endothelial and smooth muscle, whereas CD45‑/CD31+/VEGFR2+ LSP cells may serve as late commitment endothelial progenitors in the adult mouse lung.
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http://dx.doi.org/10.3892/ijmm.2019.4053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365051PMC
March 2019

The application of frequency-domain photoacoustics to temperature-dependent measurements of the Grüneisen parameter in lipids.

Photoacoustics 2018 Sep 3;11:56-64. Epub 2018 Aug 3.

Center for Advanced Diffusion-Wave and Photoacoustic Technologies (CADIPT), Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, M5S 3G8, Canada.

The Grüneisen parameter is an essential factor in biomedical photoacoustic (PA) diagnostics. In most PA imaging applications, the variation of the Grüneisen parameter with tissue type is insignificant. This is not the case for PA imaging and characterization of lipids, as they have a very distinct Grüneisen parameter compared with other tissue types. One example of PA applications involving lipids is the imaging and characterization of atherosclerotic plaques. Intravascular photoacoustic (IVPA) imaging is a promising diagnostic tool that can evaluate both plaque severity and composition. The literature for IVPA has mainly focused on using the difference in absorption coefficients between plaque components and healthy arterial tissues. However, the Grüneisen parameters for lipids and their behavior with temperature have not been well established in the literature. In this study we employ frequency-domain photoacoustic measurements to estimate the Grüneisen parameter by virtue of the ability of this modality to independently measure the absorption coefficient and the Grüneisen parameter through the use of the phase channel. The values of the Grüneisen parameters of some lipids are calculated as functions of temperature in the range 25-45 °C.
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http://dx.doi.org/10.1016/j.pacs.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091231PMC
September 2018

Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability.

Cancer Immunol Res 2018 09 18;6(9):1025-1038. Epub 2018 Jun 18.

Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.

Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses. Here, we expanded upon these findings and mechanistically dissected the properties that contribute to the potency of this amphiphile-vaccine (amph-vaccine). We found that multiple linkage chemistries could be used to link peptides with DSPE-PEG, and further, that multiple albumin-binding moieties conjugated to peptide antigens enhanced LN accumulation and subsequent T-cell priming. In addition to enhancing lymphatic trafficking, DSPE-PEG conjugation increased the stability of peptides in serum. DSPE-PEG peptides trafficked beyond immediate draining LNs to reach distal nodes, with antigen presented for at least a week , whereas soluble peptide presentation quickly decayed. Responses to amph-vaccines were not altered in mice deficient in the albumin-binding neonatal Fc receptor (FcRn), but required -dependent dendritic cells (DCs). Amph-peptides were processed by human DCs equivalently to unmodified peptides. These data define design criteria for enhancing the immunogenicity of molecular vaccines to guide the design of next-generation peptide vaccines. .
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http://dx.doi.org/10.1158/2326-6066.CIR-17-0607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247902PMC
September 2018

Modular Peptide Amphiphile Micelles Improving an Antibody-Mediated Immune Response to Group A Streptococcus.

ACS Biomater Sci Eng 2017 28;3(2):144-152. Epub 2016 Sep 28.

Institute for Molecular Engineering, University of Chicago, William Eckhardt Research Center, 5640 S. Ellis Avenue, Chicago, Illinois 60637, United States.

Inducing a strong and specific immune response is the hallmark of a successful vaccine. Nanoparticles have emerged as promising vaccine delivery devices to discover and elicit immune responses. Fine-tuning a nanoparticle vaccine to create an immune response with specific antibody and other cellular responses is influenced by many factors such as shape, size, and composition. Peptide amphiphile micelles are a unique biomaterials platform that can function as a modular vaccine delivery system, enabling control over many of these important factors and delivering payloads more efficiently to draining lymph nodes. In this study, the modular properties of peptide amphiphile micelles are utilized to improve an immune response against a Group A Streptococcus B cell antigen (J8). The hydrophobic/hydrophilic interface of peptide amphiphile micelles enabled the precise entrapment of amphiphilic adjuvants which were found to not alter micelle formation or shape. These heterogeneous micelles significantly enhanced murine antibody responses when compared to animals vaccinated with nonadjuvanted micelles or soluble J8 peptide supplemented with a classical adjuvant. The heterogeneous micelle induced antibodies also showed cross-reactivity with wild-type Group A Streptococcus providing evidence that micelle-induced immune responses are capable of identifying their intended pathogenic targets.
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http://dx.doi.org/10.1021/acsbiomaterials.6b00422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726538PMC
September 2016

The mouse passive-transfer model of MuSK myasthenia gravis: disrupted MuSK signaling causes synapse failure.

Ann N Y Acad Sci 2018 01 10;1412(1):54-61. Epub 2017 Nov 10.

Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia.

While the majority of myasthenia gravis patients express antibodies targeting the acetylcholine receptor, the second most common cohort instead displays autoantibodies against muscle-specific kinase (MuSK). MuSK is a transmembrane tyrosine kinase found in the postsynaptic membrane of the neuromuscular junction. During development, MuSK serves as a signaling hub, coordinating the alignment of the pre- and postsynaptic components of the synapse. Adult mice that received repeated daily injections of IgG from anti-MuSK myasthenia gravis patients developed muscle weakness, associated with neuromuscular transmission failure. MuSK autoantibodies are predominantly of the IgG4 type. They suppress the kinase activity of MuSK and the phosphorylation of target proteins in the postsynaptic membrane. Loss of postsynaptic acetylcholine receptors is the primary cause of neuromuscular transmission failure. MuSK autoantibodies also disrupt the capacity of the motor nerve terminal to adaptively increase acetylcholine release in response to the reduced postsynaptic responsiveness to acetylcholine. The passive IgG transfer model of MuSK myasthenia gravis has been used to test candidate treatments. Pyridostigmine, a first-line cholinesterase inhibitor drug, exacerbated the disease process, while 3,4-diaminopyridine and albuterol were found to be beneficial in this mouse model.
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http://dx.doi.org/10.1111/nyas.13513DOI Listing
January 2018

[Differentiation of Cultivated CD45/CD31 Mouse Lung Side Population Cells into Vascular Smooth Muscle Cells ].

Sichuan Da Xue Xue Bao Yi Xue Ban 2017 May;48(3):363-367

Department of Biochemistry and Molecular Biology , Jinzhou Medical University, Jinzhou 121000, China.

Objectives: To investigate the characteristics of differentiation of lung side population cells (LSP cells).

Methods: CD45/CD31 LSP cells sorted by flow cytometry were taken from mouse lung tissues and cultured for 14 d. The cultured LSP cells were observed with colony formation assay and flow cytometry. The mRNA expressions of ATP-binding cassette transporter G2 (), smooth muscle actin () and α-smooth muscle tropomyosin () in both freshly isolated LSP cells and cultured LSP cells were examined. The expressions of ABCG2 and stem cell antigen 1 (Sca1) in LSP cells were detected using immunofluorescence. RT-PCR tests were performed to detect the expressions of ABCG2, SMA and α-SMT in LSP cells.

Results: The isolated CD45/CD31 lung side population cells expressed ABCG2, and Sca1, but not . A large number of LSP in aggregated state were observed after 14 d of culture. Before induction of differentiation, the CD45/CD31 LSP cells expressed and , but not α-SMT. After induction of differentiation, the CD45/CD31 lung side population cells expressed α-SMT and , but not .

Conclusions: CD45/CD31 LSP cells might be progenitor cells of vascular smooth muscle cells, possessing the characteristics of stem cell differentiations.
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May 2017

Proliferation, differentiation and migration of SCA1/CD31 cardiac side population cells in vitro and in vivo.

Int J Cardiol 2017 Jan 9;227:378-386. Epub 2016 Nov 9.

Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou 121000, China.. Electronic address:

Background: Side-population (SP) cells, identified by their capacity to efflux Hoechst dye, are highly enriched for stem/progenitor cell activity. They are found in many mammalian tissues, including mouse heart. Studies suggest that cardiac SP (CSP) cells can be divided into SCA1/CD31, SCA1/CD31 and SCA1/CD31 CSP subpopulations. SCA1/CD31 were shown to be cardiac and endothelial stem/progenitors while SCA1/CD31 CSP cells are endothelial progenitors. SCA1/CD31 CSP cells remain to be fully characterized. In this study, we characterized SCA1/CD31 CSP cells in the adult mouse heart, and investigated their abilities to proliferate, differentiate and migrate in vitro and in vivo.

Methods And Results: Using fluorescence-activated cell sorting, reverse transcriptase/polymerase chain reaction, assays of cell proliferation, differentiation and migration, and a murine model of myocardial infarction we show that SCA1/CD31 CSP cells are located in the heart mesenchyme and express genes characteristic of stem cells and endothelial progenitors. These cells were capable of proliferation, differentiation, migration and vascularization in vitro and in vivo. Following experimental myocardial infarction, the SCA1/CD31 CSP cells migrated from non-infarcted areas to the infarcted region within the myocardium where they differentiated into endothelial cells forming vascular (tube-like) structures. We further demonstrated that the SDF-1α/CXCR4 pathway may play an important role in migration of these cells after myocardial infarction.

Conclusions: Based on their gene expression profile, localization and ability to proliferate, differentiate, migrate and vascularize in vitro and in vivo, we conclude that SCA1/CD31 CSP cells may serve as endothelial progenitor cells in the adult mouse heart.
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http://dx.doi.org/10.1016/j.ijcard.2016.11.047DOI Listing
January 2017

Forced expression of muscle specific kinase slows postsynaptic acetylcholine receptor loss in a mouse model of MuSK myasthenia gravis.

Physiol Rep 2015 Dec 22;3(12). Epub 2015 Dec 22.

Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, Australia

We investigated the influence of postsynaptic tyrosine kinase signaling in a mouse model of muscle-specific kinase (MuSK) myasthenia gravis (MG). Mice administered repeated daily injections of IgG from MuSK MG patients developed impaired neuromuscular transmission due to progressive loss of acetylcholine receptor (AChR) from the postsynaptic membrane of the neuromuscular junction. In this model, anti-MuSK-positive IgG caused a reduction in motor endplate immunolabeling for phosphorylated Src-Y418 and AChR β-subunit-Y390 before any detectable loss of MuSK or AChR from the endplate. Adeno-associated viral vector (rAAV) encoding MuSK fused to enhanced green fluorescent protein (MuSK-EGFP) was injected into the tibialis anterior muscle to increase MuSK synthesis. When mice were subsequently challenged with 11 daily injections of IgG from MuSK MG patients, endplates expressing MuSK-EGFP retained more MuSK and AChR than endplates of contralateral muscles administered empty vector. Recordings of compound muscle action potentials from myasthenic mice revealed less impairment of neuromuscular transmission in muscles that had been injected with rAAV-MuSK-EGFP than contralateral muscles (empty rAAV controls). In contrast to the effects of MuSK-EGFP, forced expression of rapsyn-EGFP provided no such protection to endplate AChR when mice were subsequently challenged with MuSK MG IgG. In summary, the immediate in vivo effect of MuSK autoantibodies was to suppress MuSK-dependent tyrosine phosphorylation of proteins in the postsynaptic membrane, while increased MuSK synthesis protected endplates against AChR loss. These results support the hypothesis that reduced MuSK kinase signaling initiates the progressive disassembly of the postsynaptic membrane scaffold in this mouse model of MuSK MG.
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http://dx.doi.org/10.14814/phy2.12658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760443PMC
December 2015

Rifampicin-dependent antibodies target glycoprotein IIb/IIIa and cause clearance of human platelets in NOD/SCID mice.

Br J Haematol 2016 Jan 29;172(1):137-40. Epub 2015 Apr 29.

Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Liaoning Medical University, Jinzhou, China.

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http://dx.doi.org/10.1111/bjh.13470DOI Listing
January 2016

Peptide amphiphile micelles self-adjuvant group A streptococcal vaccination.

AAPS J 2015 Mar 20;17(2):380-8. Epub 2014 Dec 20.

Biomolecular Science and Engineering Program, University of California, Santa Barbara, California, 93106, USA.

Delivery system design and adjuvant development are crucially important areas of research for improving vaccines. Peptide amphiphile micelles are a class of biomaterials that have the unique potential to function as both vaccine delivery vehicles and self-adjuvants. In this study, peptide amphiphiles comprised of a group A streptococcus B cell antigen (J8) and a dialkyl hydrophobic moiety (diC16) were synthesized and organized into self-assembled micelles, driven by hydrophobic interactions among the alkyl tails. J8-diC16 formed cylindrical micelles with highly α-helical peptide presented on their surfaces. Both the micelle length and secondary structure were shown to be enhanced by annealing. When injected into mice, J8-diC16 micelles induced a strong IgG1 antibody response that was comparable to soluble J8 peptide supplemented with two classical adjuvants. It was discovered that micelle adjuvanticity requires the antigen be a part of the micelle since separation of J8 and the micelle was insufficient to induce an immune response. Additionally, the diC16 tail appears to be non-immunogenic since it does not stimulate a pathogen recognition receptor whose agonist (Pam3Cys) possesses a very similar chemical structure. The research presented in this paper demonstrates the promise peptide amphiphile micelles have in improving the field of vaccine engineering.
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http://dx.doi.org/10.1208/s12248-014-9707-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365084PMC
March 2015

Muscle-specific kinase (MuSK) autoantibodies suppress the MuSK pathway and ACh receptor retention at the mouse neuromuscular junction.

J Physiol 2014 Jul 23;592(13):2881-97. Epub 2014 May 23.

Physiology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006, Australia

Muscle-specific kinase (MuSK) autoantibodies from myasthenia gravis patients can block the activation of MuSK in vitro and/or reduce the postsynaptic localization of MuSK. Here we use a mouse model to examine the effects of MuSK autoantibodies upon some key components of the postsynaptic MuSK pathway and upon the regulation of junctional ACh receptor (AChR) numbers. Mice became weak after 14 daily injections of anti-MuSK-positive patient IgG. The intensity and area of AChR staining at the motor endplate was markedly reduced. Pulse-labelling of AChRs revealed an accelerated loss of pre-existing AChRs from postsynaptic AChR clusters without a compensatory increase in incorporation of (newly synthesized) replacement AChRs. Large, postsynaptic AChR clusters were replaced by a constellation of tiny AChR microaggregates. Puncta of AChR staining also appeared in the cytoplasm beneath the endplate. Endplate staining for MuSK, activated Src, rapsyn and AChR were all reduced in intensity. In the tibialis anterior muscle there was also evidence that phosphorylation of the AChR β-subunit-Y390 was reduced at endplates. In contrast, endplate staining for β-dystroglycan (through which rapsyn couples AChR to the synaptic basement membrane) remained intense. The results suggest that anti-MuSK IgG suppresses the endplate density of MuSK, thereby down-regulating MuSK signalling activity and the retention of junctional AChRs locally within the postsynaptic membrane scaffold.
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http://dx.doi.org/10.1113/jphysiol.2013.270207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221826PMC
July 2014

Migration of resident cardiac stem cells in myocardial infarction.

Anat Rec (Hoboken) 2013 Feb 5;296(2):184-91. Epub 2012 Dec 5.

Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Liaoning Medical University, Jinzhou City, Liaoning 121001, People's Republic of China.

Ischemic heart disease is a major cause of morbidity and mortality worldwide. Stem cell-based therapy, which aims to restore cardiac structure and function by regeneration of functional myocardium, has recently been proposed as a novel alternative treatment modality. Resident cardiac stem cells (CSCs) in adult hearts are a key cell type under investigation. CSCs have been shown to be able to repair damaged myocardium and improve myocardial function in both human and animal studies. This approach relies not only on the proliferation of the CSCs, but also upon their migration to the site of injury within the heart. Here, we briefly review reported CSC populations and discuss signaling factors and pathways required for the migration of CSCs.
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http://dx.doi.org/10.1002/ar.22633DOI Listing
February 2013

Polysaccharides from the root of Angelica sinensis promotes hematopoiesis and thrombopoiesis through the PI3K/AKT pathway.

BMC Complement Altern Med 2010 Dec 21;10:79. Epub 2010 Dec 21.

Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.

Background: Dozens of Traditional Chinese Medicine (TCM) formulas have been used for promotion of "blood production" for centuries, and we are interested in developing novel thrombopoietic medicines from these TCMs. Our previous studies have demonstrated the hematopoietic effects of DangGui BuXue Tong (DBT), a formula composed of Radix Angelicae Sinensis and Radix Astragali in animal and cellular models. As a step further to identify and characterize the active chemical components of DBT, we tested the hematopoietic and particularly, thrombopoietic effects of polysaccharide-enriched fractions from the root of Radix Angelicae Sinensis (APS) in this study.

Methods: A myelosuppression mouse model was treated with APS (10 mg/kg/day). Peripheral blood cells from APS, thrombopoietin and vehicle-treated samples were then counted at different time-points. Using the colony-forming unit (CFU) assays, we determined the effects of APS on the proliferation and differentiation of hematopoietic stem/progenitor cells and megakaryocytic lineages. Using a megakaryocytic cell line M-07e as model, we analyzed the cellular apoptosis progression with and without APS treatment by Annexin V, Mitochondrial Membrane Potential and Caspase 3 assays. Last, the anti-apoptotic effect of APS on cells treated with Ly294002, a Phosphatidylinositol 3-Kinse inhibitor (PI3K) was also tested.

Results: In animal models, APS significantly enhanced not only the recovery of platelets, other blood cells and their progenitor cells, but also the formation of Colony Forming Unit (CFU). In M-07e cells, we observed the anti-apoptotic effect of APS. Treatment by Ly294002 alone increased the percentage of cells undergoing apoptosis. However, addition of APS to Ly294002-treated cells significantly reduced the percentage of cells undergoing apoptosis.

Conclusions: APS promotes hematopoiesis and thrombopoiesis in the mouse model. This effect likely resulted from the anti-apoptosis activity of APS and is likely to involve the PI3K/AKT pathway.
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http://dx.doi.org/10.1186/1472-6882-10-79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3022894PMC
December 2010

Drug-induced thrombocytopenia: development of a novel NOD/SCID mouse model to evaluate clearance of circulating platelets by drug-dependent antibodies and the efficacy of IVIG.

Blood 2010 Sep 21;116(11):1958-60. Epub 2010 Jun 21.

St George Clinical School, University of New South Wales, Sydney, Australia.

Drug-induced immune thrombocytopenia (DITP) is an adverse drug effect mediated by drug-dependent antibodies. Intravenous immunoglobulin (IVIG) is frequently used to treat DITP and primary immune thrombocytopenia (ITP). Despite IVIG's proven beneficial effects in ITP, its efficacy in DITP is unclear. We have established a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of DITP in which human platelets survive for more than 24 hours, allowing platelet clearance by DITP/ITP antibodies to be studied. Rapid human platelet clearance was uniformly observed with all quinine-induced thrombocytopenia (QITP) patient sera studied (mean platelet lifespans: QITP 1.5 ± 0.3 hours vs controls 16.5 ± 4.3 hours), consistent with the clinical presentation of DITP. In contrast, clearance rates with ITP antibodies were more variable. IVIG treatment partially prevented platelet clearance by DITP and ITP antibodies. Our results suggest that the NOD/SCID mouse model is useful for investigating the efficacy of current and future DITP therapies, an area in which there is little experimental evidence to guide treatment.
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http://dx.doi.org/10.1182/blood-2010-02-268326DOI Listing
September 2010

Differentiation and migration of Sca1+/CD31- cardiac side population cells in a murine myocardial ischemic model.

Int J Cardiol 2010 Jan 28;138(1):40-9. Epub 2009 Feb 28.

Center for Vascular Research, Department of Medicine and Hematology, St George Hospital, St George Clinical School, University of New South Wales, Sydney, 2052, Australia.

Background: Side population cells are a rare subset of cells found in the adult heart that are highly enriched for stem and progenitor cell activity. Recent studies have suggested that Sca1+/CD31- cardiac side population cells are capable of differentiation into cardiomyocytes in vitro. However, the response of these cells to myocardial injury remains unknown in vivo.

Methods: Sca1+/CD31- cardiac side population cells were isolated from mouse (C57BL6/J) hearts by FACS. These cells were labeled and delivered via an intramyocardial injection into an infracted mouse heart. The differentiation potential of these cells was determined by immunohistochemistry two weeks later. We further tested the migration potential and the relationship of SDF-1alpha/CXCR4 to these cells.

Results: The transplanted cells were found to express cardiomyocyte or endothelial cell specific markers. Furthermore, when these cells were transplanted into non-infarct myocardium after myocardial infarction, they were found in the damaged myocardium. Consistent with their homing property, we found that SDF-1alpha and CXCR4 were up-regulated in the damaged myocardium and on Sca1+/CD31- cardiac side population cells respectively following myocardial infarction. We also show that SDF-1alpha induced migration of Sca1+/CD31- cardiac side population cells in vitro.

Conclusions: Our results have suggested that Sca1+/CD31- cardiac side population cells are able to migrate into damaged myocardium from non-ischemic area of the heart and differentiate into both cardiomyocyte- and endothelial-like cells following acute ischemic injury. The SDF-1alpha/CXCR4 system might play an important role in the migration of these cells.
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http://dx.doi.org/10.1016/j.ijcard.2008.08.032DOI Listing
January 2010

Gene expression profiling and localization of Hoechst-effluxing CD45- and CD45+ cells in the embryonic mouse lung.

Physiol Genomics 2005 Oct 2;23(2):172-81. Epub 2005 Aug 2.

Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Hoechst-effluxing cells (side population cells) are a rare subset of cells found in adult tissues that are highly enriched for stem and progenitor cell activity. To identify potential stem and progenitor cells during lung development, we generated gene expression profiles for CD45- and CD45+ side population cells in the embryonic day 17.5 lung. We found that side population cells comprise 1% of total embryonic day 17.5 lung cells (55% CD45+, 45% CD45-). Gene profiling data demonstrated an overrepresentation of endothelial genes within the CD45- side population. We used expression of several distinct genes to identify two types of CD45- side population cells: 1) von Willebrand factor+/smooth muscle actin+ cells that reside in the muscular layer of select large vessels and 2) von Willebrand factor+/intercellular adhesion molecule+ cells that reside within the endothelial layer of select small vessels. Gene profiling of the CD45+ side population indicated an overrepresentation of genes associated with myeloid cell differentiation. Consistent with this, culturing CD45+ side population cells was associated with induction of mature dendritic markers (CD86). The microarray results suggested that expression of myeloperoxidase and proteinase-3 might be used to identify CD45+ side population cells. By immunohistochemistry, we found that myeloperoxidase+/proteinase-3+ cells represent a small subset of total CD45+ cells in the embryonic day 17.5 lung and that they reside in the mesenchyme and perivascular regions. This is the first detailed information regarding the phenotype and localization of side population cells in a developing organ.
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http://dx.doi.org/10.1152/physiolgenomics.00059.2005DOI Listing
October 2005

Embryonic lung side population cells are hematopoietic and vascular precursors.

Am J Respir Cell Mol Biol 2005 Jul 31;33(1):32-40. Epub 2005 Mar 31.

The Pulmonary Center, Boston University School of Medicine, MA 02118, USA.

Side population (SP) cells are a select cell population identified by a capacity to efflux Hoechst dye that are highly enriched for stem/progenitor cell activity. In this study, we found that SP cells comprised of CD45(+) and CD45(-) subtypes are present in the embryonic lung (E-SP) at levels varying with gestational age. Long-term in vivo competitive blood reconstitution studies demonstrated that hematopoeitic stem cell capacity resided within the CD45(+) E-SP cell subset. Immunophenotyping of CD45(-) E-SP cells determined that this population consists of two subtypes: CD31(-) and CD31(+). Limited gene expression profiling indicated that CD45(-)/CD31(-) E-SP cells have features of smooth muscle precursors, and give rise to smooth muscle in culture. On the other hand, CD45(-)/CD31(+) E-SP cells express genes characteristic of endothelium, but by themselves do not grow or differentiate in culture. Co-culture of CD45(-)/CD31(+) and CD45(-)/CD31(-) E-SP cells, however, resulted in the formation of complex tubular networks that express markers of endothelium. Together, these findings illustrate that embryonic lung SP cells are heterogeneous, composed of hematopoeitic and nonhematopoeitic progenitors, and may play a key role in the formation of the lung vasculature.
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http://dx.doi.org/10.1165/rcmb.2005-0024OCDOI Listing
July 2005