Publications by authors named "Andrew Zannettino"

176 Publications

Chondrogenic preconditioning of mesenchymal stem/stromal cells within a magnetic scaffold for osteochondral repair.

Biofabrication 2022 03 14;14(2). Epub 2022 Mar 14.

School of Chemical Engineering, The University of Adelaide, Adelaide, SA 5005, Australia.

Stem cell therapy using mesenchymal stem/stromal cells (MSCs) represents a novel approach to treating severe diseases, including osteoarthritis. However, the therapeutic benefit of MSCs is highly dependent on their differentiation state, which can be regulated by many factors. Herein, three-dimensional (3D) magnetic scaffolds were successfully fabricated by incorporating magnetic nanoparticles (MNPs) into electrospun gelatin nanofibers. When positioned near a rotating magnet (= 0.5 Hz), the magnetic scaffolds with the embedded MSCs were driven upward/downward in the culture container, which induced mechanical stimulation to MSCs due to spatial confinement and fluid flow. The extracellular matrix-mimicking scaffold and the alternating magnetic field significantly enhanced chondrogenesis instead of osteogenesis. Furthermore, the fiber topography could be tuned with different compositions of the coating layer on MNPs, and the topography had a significant impact on MSC differentiation. Selective up-regulation of chondrogenesis-related genes (and) was found for the magnetic scaffolds with citric acid-coated MNPs (CAG). In contrast, osteogenesis-related genes (and) were selectively and significantly up-regulated for the magnetic scaffolds with polyvinylpyrrolidone-coated MNPs. Prior to implantation, chondrogenic preconditioning of MSCs within the CAG scaffolds under a dynamic magnetic field resulted in superior osteochondral repair. Hence, the magnetic scaffolds together with an in-house rotating magnet device could be a novel platform to initiate multiple stimuli on stem cell differentiation for effective repair of osteochondral defects.
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http://dx.doi.org/10.1088/1758-5090/ac5935DOI Listing
March 2022

Fragmentation of tissue-resident macrophages during isolation confounds analysis of single-cell preparations from mouse hematopoietic tissues.

Cell Rep 2021 11;37(8):110058

Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia. Electronic address:

Mouse hematopoietic tissues contain abundant tissue-resident macrophages that support immunity, hematopoiesis, and bone homeostasis. A systematic strategy to characterize macrophage subsets in mouse bone marrow (BM), spleen, and lymph node unexpectedly reveals that macrophage surface marker staining emanates from membrane-bound subcellular remnants associated with unrelated cells. Intact macrophages are not present within these cell preparations. The macrophage remnant binding profile reflects interactions between macrophages and other cell types in vivo. Depletion of CD169 macrophages in vivo eliminates F4/80 remnant attachment. Remnant-restricted macrophage-specific membrane markers, cytoplasmic fluorescent reporters, and mRNA are all detected in non-macrophage cells including isolated stem and progenitor cells. Analysis of RNA sequencing (RNA-seq) data, including publicly available datasets, indicates that macrophage fragmentation is a general phenomenon that confounds bulk and single-cell analysis of disaggregated hematopoietic tissues. Hematopoietic tissue macrophage fragmentation undermines the accuracy of macrophage ex vivo molecular profiling and creates opportunity for misattribution of macrophage-expressed genes to non-macrophage cells.
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http://dx.doi.org/10.1016/j.celrep.2021.110058DOI Listing
November 2021

Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia.

Intern Med J 2021 Oct;51(10):1707-1712

Department of Clinical Haematology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.
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http://dx.doi.org/10.1111/imj.15457DOI Listing
October 2021

Desmoglein-2 expression is an independent predictor of poor prognosis patients with multiple myeloma.

Mol Oncol 2022 03 24;16(6):1221-1240. Epub 2021 Jul 24.

Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.

Multiple myeloma (MM) is the second most common haematological malignancy and is an incurable disease of neoplastic plasma cells (PC). Newly diagnosed MM patients currently undergo lengthy genetic testing to match chromosomal mutations with the most potent drug/s to decelerate disease progression. With only 17% of MM patients surviving 10-years postdiagnosis, faster detection and earlier intervention would unequivocally improve outcomes. Here, we show that the cell surface protein desmoglein-2 (DSG2) is overexpressed in ~ 20% of bone marrow biopsies from newly diagnosed MM patients. Importantly, DSG2 expression was strongly predictive of poor clinical outcome, with patients expressing DSG2 above the 70 percentile exhibiting an almost 3-fold increased risk of death. As a prognostic factor, DSG2 is independent of genetic subtype as well as the routinely measured biomarkers of MM activity (e.g. paraprotein). Functional studies revealed a nonredundant role for DSG2 in adhesion of MM PC to endothelial cells. Together, our studies suggest DSG2 to be a potential cell surface biomarker that can be readily detected by flow cytometry to rapidly predict disease trajectory at the time of diagnosis.
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http://dx.doi.org/10.1002/1878-0261.13055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8936512PMC
March 2022

Plant-derived soybean peroxidase stimulates osteoblast collagen biosynthesis, matrix mineralization, and accelerates bone regeneration in a sheep model.

Bone Rep 2021 Jun 27;14:101096. Epub 2021 May 27.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.

Bone defects arising from fractures or disease represent a significant problem for surgeons to manage and are a substantial economic burden on the healthcare economy. Recent advances in the development of biomaterial substitutes provides an attractive alternative to the current "gold standard" autologous bone grafting. Despite on-going research, we are yet to identify cost effective biocompatible, osteo-inductive factors that stimulate controlled, accelerated bone regeneration.We have recently reported that enzymes with peroxidase activity possess previously unrecognised roles in extracellular matrix biosynthesis, angiogenesis and osteoclastogenesis, which are essential processes in bone remodelling and repair. Here, we report for the first time, that plant-derived soybean peroxidase (SBP) possesses pro-osteogenic ability by promoting collagen I biosynthesis and matrix mineralization of human osteoblasts . Mechanistically, SBP regulates osteogenic genes responsible for inflammation, extracellular matrix remodelling and ossification, which are necessary for normal bone healing. Furthermore, SBP was shown to have osteo-inductive properties, that when combined with commercially available biphasic calcium phosphate (BCP) granules can accelerate bone repair in a critical size long bone defect ovine model. Micro-CT analysis showed that SBP when combined with commercially available biphasic calcium phosphate (BCP) granules significantly increased bone formation within the defects as early as 4 weeks compared to BCP alone. Histomorphometric assessment demonstrated accelerated bone formation prominent at the defect margins and surrounding individual BCP granules, with evidence of intramembranous ossification. These results highlight the capacity of SBP to be an effective regulator of osteoblastic function and may be beneficial as a new and cost effective osteo-inductive agent to accelerate repair of large bone defects.
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http://dx.doi.org/10.1016/j.bonr.2021.101096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178086PMC
June 2021

The stem cell revolution: on the role of CD164 as a human stem cell marker.

NPJ Regen Med 2021 Jun 8;6(1):33. Epub 2021 Jun 8.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.

Accurately defining hierarchical relationships between human stem cells and their progeny, and using this knowledge for new cellular therapies, will undoubtedly lead to further successful treatments for life threatening and chronic diseases, which represent substantial burdens on patient quality of life and to healthcare systems globally. Clinical translation relies in part on appropriate biomarker, in vitro manipulation and transplantation strategies. CD164 has recently been cited as an important biomarker for enriching both human haematopoietic and skeletal stem cells, yet a thorough description of extant human CD164 monoclonal antibody (Mab) characteristics, which are critical for identifying and purifying these stem cells, was not discussed in these articles. Here, we highlight earlier but crucial research describing these relevant characteristics, including the differing human CD164 Mab avidities and their binding sites on the human CD164 sialomucin, which importantly may affect subsequent stem cell function and fate.
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http://dx.doi.org/10.1038/s41536-021-00143-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187384PMC
June 2021

Deletion of in Preosteoblasts Reveals a Role for the Mammalian Target of Rapamycin Complex 1 (mTORC1) Complex in Dietary-Induced Changes to Bone Mass and Glucose Homeostasis in Female Mice.

JBMR Plus 2021 May 24;5(5):e10486. Epub 2021 Mar 24.

Adelaide Medical School, Faculty of Health and Medical Science University of Adelaide Adelaide South Australia Australia.

The mammalian target of rapamycin complex 1 (mTORC1) complex is the major nutrient sensor in mammalian cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, to control anabolic and catabolic processes. We have recently shown that suppression of the mTORC1 complex in bone-forming osteoblasts (OBs) improved glucose handling in male mice fed a normal or obesogenic diet. Mechanistically, this occurs, at least in part, by increasing OB insulin sensitivity leading to upregulation of glucose uptake and glycolysis. Given previously reported sex-dependent differences observed upon antagonism of mTORC1 signaling, we investigated the metabolic and skeletal effects of genetic inactivation of preosteoblastic-mTORC1 in female mice. Eight-week-old control diet (CD)-fed mice had a low bone mass with a significant reduction in trabecular bone volume and trabecular number, reduced cortical bone thickness, and increased marrow adiposity. Despite no changes in body composition, CD-fed mice exhibited significant lower fasting insulin and glucose levels and increased insulin sensitivity. Upon high-fat diet (HFD) feeding, mice were resistant to a diet-induced increase in whole-body and total fat mass and protected from the development of diet-induced insulin resistance. Notably, although 12 weeks of HFD increased marrow adiposity, with minimal changes in both trabecular and cortical bone in the female control mice, marrow adiposity was significantly reduced in HFD-fed compared to both HFD-fed control and CD-fed mice. Collectively, our results demonstrate that mTORC1 function in preosteoblasts is crucial for skeletal development and skeletal regulation of glucose homeostasis in both male and female mice. Importantly, loss of mTORC1 function in OBs results in metabolic and physiological adaptations that mirror a caloric restriction phenotype (under CD) and protects against HFD-induced obesity, associated insulin resistance, and marrow adiposity expansion. These results highlight the critical contribution of the skeleton in the regulation of whole-body energy homeostasis. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101617PMC
May 2021

CKLF and IL1B transcript levels at diagnosis are predictive of relapse in children with pre-B-cell acute lymphoblastic leukaemia.

Br J Haematol 2021 04 23;193(1):171-175. Epub 2021 Feb 23.

Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, SA, Australia.

Disease relapse is the greatest cause of treatment failure in paediatric B-cell acute lymphoblastic leukaemia (B-ALL). Current risk stratifications fail to capture all patients at risk of relapse. Herein, we used a machine-learning approach to identify B-ALL blast-secreted factors that are associated with poor survival outcomes. Using this approach, we identified a two-gene expression signature (CKLF and IL1B) that allowed identification of high-risk patients at diagnosis. This two-gene expression signature enhances the predictive value of current at diagnosis or end-of-induction risk stratification suggesting the model can be applied continuously to help guide implementation of risk-adapted therapies.
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http://dx.doi.org/10.1111/bjh.17161DOI Listing
April 2021

The revival of dithiocarbamates: from pesticides to innovative medical treatments.

iScience 2021 Feb 22;24(2):102092. Epub 2021 Jan 22.

Richter Lab, Department of Surgery, Basil Hetzel Institute for Translational Health Research, University of Adelaide, Adelaide, SA 5011, Australia.

Dithiocarbamates (DTCs) have been used for various applications, including as hardening agents in rubber manufacturing, as fungicide in agriculture, and as medications to treat alcohol misuse disorder. The multi-faceted effects of DTCs rely mainly on metal binding abilities and a high reactivity with thiol groups. Therefore, the list of potential applications is still increasing, exemplified by the US Food and Drug Administration approval of disulfiram (Antabuse) and its metabolite diethyldithiocarbamate in clinical trials against cancer, human immunodeficiency virus, and Lyme disease, as well as new DTC-related compounds that have been synthesized to target diseases with unmet therapeutic needs. In this review, we will discuss the latest progress of DTCs as anti-cancer agents and provide a summary of the mechanisms of action. We will explain the expansion of DTCs' activity in the fields of microbiology, neurology, cardiology, and ophthalmology, thereby providing evidence for the important role and therapeutic potential of DTCs as innovative medical treatments.
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http://dx.doi.org/10.1016/j.isci.2021.102092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868997PMC
February 2021

The mTORC1 complex in pre-osteoblasts regulates whole-body energy metabolism independently of osteocalcin.

Bone Res 2021 Feb 8;9(1):10. Epub 2021 Feb 8.

Adelaide Medical School, Faculty of Health and Medical Science, University of Adelaide, Adelaide, 5005, SA, Australia.

Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation of insulin signaling and development of insulin resistance. In osteoblasts (OBs), insulin signaling plays a crucial role in the control of systemic glucose homeostasis. We utilized mice with conditional deletion of Rptor to investigate how the loss of mTORC1 function in OB affects glucose metabolism under normal and overnutrition dietary states. Compared to the controls, chow-fed Rptor mice had substantially less fat mass and exhibited adipocyte hyperplasia. Remarkably, upon feeding with high-fat diet, mice with pre- and post-natal deletion of Rptor in OBs were protected from diet-induced obesity and exhibited improved glucose metabolism with lower fasting glucose and insulin levels, increased glucose tolerance and insulin sensitivity. This leanness and resistance to weight gain was not attributable to changes in food intake, physical activity or lipid absorption but instead was due to increased energy expenditure and greater whole-body substrate flexibility. RNA-seq revealed an increase in glycolysis and skeletal insulin signaling pathways, which correlated with the potentiation of insulin signaling and increased insulin-dependent glucose uptake in Rptor-knockout osteoblasts. Collectively, these findings point to a critical role for the mTORC1 complex in the skeletal regulation of whole-body glucose metabolism and the skeletal development of insulin resistance.
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http://dx.doi.org/10.1038/s41413-020-00123-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868369PMC
February 2021

Macrophages in multiple myeloma: key roles and therapeutic strategies.

Cancer Metastasis Rev 2021 03 6;40(1):273-284. Epub 2021 Jan 6.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.

Macrophages are a vital component of the tumour microenvironment and crucial mediators of tumour progression. In the last decade, significant strides have been made in understanding the crucial functional roles played by macrophages in the development of the plasma cell (PC) malignancy, multiple myeloma (MM). Whilst the interaction between MM PC and stromal cells within the bone marrow (BM) microenvironment has been extensively studied, we are only just starting to appreciate the multifaceted roles played by macrophages in disease progression. Accumulating evidence demonstrates that macrophage infiltration is associated with poor overall survival in MM. Indeed, macrophages influence numerous pathways critical for the initiation and progression of MM, including homing of malignant cells to BM, tumour cell growth and survival, drug resistance, angiogenesis and immune suppression. As such, therapeutic strategies aimed at targeting macrophages within the BM niche have promise in the clinical setting. This review will discuss the functions elicited by macrophages throughout different stages of MM and provide a comprehensive evaluation of potential macrophage-targeted therapies.
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http://dx.doi.org/10.1007/s10555-020-09943-1DOI Listing
March 2021

Tumour Dissemination in Multiple Myeloma Disease Progression and Relapse: A Potential Therapeutic Target in High-Risk Myeloma.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Myeloma Research Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, The University of Australia, Adelaide 5005, Australia.

Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a feature of advanced disease. In this review, the current understanding of the process of MM PC dissemination and the extrinsic and intrinsic factors potentially driving it are addressed through analysis of patient-derived MM PCs and MM cell lines as well as mouse models of homing and dissemination. In addition, we discuss how patient cytogenetic subgroups that present with highly disseminated disease, such as t(4;14), t(14;16) and t(14;20), suggest that intrinsic properties of MM PC influence their ability to disseminate. Finally, we discuss the possibility of using therapeutic targeting of tumour dissemination to slow disease progression and prevent overt relapse.
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http://dx.doi.org/10.3390/cancers12123643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761917PMC
December 2020

The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

Gastroenterology 2021 03 14;160(4):1224-1239.e30. Epub 2020 Nov 14.

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.

Background & Aims: Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored.

Methods: Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC.

Results: We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5 intestinal stem cell differentiation. Finally, adeno-associated virus 8 (AAV8)-mediated delivery of Islr to hepatocytes increased BMP signaling and improved survival in our mouse model of hepatic metastasis.

Conclusions: Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.
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http://dx.doi.org/10.1053/j.gastro.2020.11.011DOI Listing
March 2021

Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells in vivo

Haematologica 2021 12 1;106(12):3176-3187. Epub 2021 Dec 1.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide.

Multiple myeloma (MM) disease progression is dependent on the ability of MM plasma cells (PCs) to egress from the bone marrow (BM), enter the circulation and disseminate to distal BM sites. Expression of the chemokine CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which overcome CXCL12-mediated retention to enable dissemination are poorly understood. We have previously identified that treatment with the CCR1 ligand CCL3 inhibits the response to CXCL12 in MM cell lines, suggesting that CCL3/CCR1 signalling may enable egress of MM PC from the BM. Here, we demonstrated that CCR1 expression was an independent prognostic indicator in newly diagnosed MM patients. Furthermore, we showed that CCR1 is a crucial driver of dissemination in vivo, with CCR1 expression in the murine MM cell line 5TGM1 being associated with an increased incidence of bone and splenic disseminated tumours in C57BL/KaLwRij mice. Furthermore, we demonstrated that CCR1 knockout in the human myeloma cell line OPM2 resulted in a >95% reduction in circulating MM PC numbers and BM and splenic tumour dissemination following intratibial injection in NSG mice. Therapeutic targeting of CCR1 with the inhibitor CCX9588 significantly reduced OPM2 or RPMI-8226 dissemination in intratibial xenograft models. Collectively, our findings suggest a novel role for CCR1 as a critical driver of BM egress of MM PCs during tumour dissemination. Furthermore, these data suggest that CCR1 may represent a potential therapeutic target for the prevention of MM tumour dissemination.
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http://dx.doi.org/10.3324/haematol.2020.253526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634189PMC
December 2021

Characterization of the role of Samsn1 loss in multiple myeloma development.

FASEB Bioadv 2020 Sep 5;2(9):554-572. Epub 2020 Aug 5.

Myeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences University of Adelaide Adelaide Australia.

The protein SAMSN1 was recently identified as a putative tumor suppressor in multiple myeloma, with re-expression of Samsn1 in the 5TGM1/KaLwRij murine model of myeloma leading to a near complete abrogation of intramedullary tumor growth. Here, we sought to clarify the mechanism underlying this finding. Intratibial administration of 5TGM1 myeloma cells into KaLwRij mice revealed that Samsn1 had no effect on primary tumor growth, but that its expression significantly inhibited the metastasis of these primary tumors. Notably, neither in vitro nor in vivo migration was affected by Samsn1 expression. Both knocking-out SAMSN1 in the RPMI-8226 and JJN3 human myeloma cell lines, and retrovirally expressing SAMSN1 in the LP-1 and OPM2 human myeloma cell lines had no effect on either cell proliferation or migration in vitro. Altering SAMSN1 expression in these human myeloma cells did not affect the capacity of the cells to establish either primary or metastatic intramedullary tumors when administered intratibially into immune deficient NSG mice. Unexpectedly, the tumor suppressive and anti-metastatic activity of Samsn1 in 5TGM1 cells were not evidenced following cell administration either intratibially or intravenously to NSG mice. Crucially, the growth of Samsn1-expressing 5TGM1 cells was limited in C57BL/6/Samsn1 mice but not in C57BL/6 Samsn1 mice. We conclude that the reported potent in vivo tumor suppressor activity of Samsn1 can be attributed, in large part, to graft-rejection from Samsn1 recipient mice. This has broad implications for the design and interpretation of experiments that utilize cancer cells and knockout mice that are mismatched for expression of specific proteins.
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http://dx.doi.org/10.1096/fba.2020-00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475304PMC
September 2020

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo.

Cancers (Basel) 2020 Aug 3;12(8). Epub 2020 Aug 3.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia.

In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that / expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls ( < 0.05, Mann-Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of , compared to stromal cells alone ( < 0.01, -test), suggesting that MM PCs promote increased expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with -overexpressing stromal cells ( < 0.01, -test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% ( < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.
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http://dx.doi.org/10.3390/cancers12082149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464474PMC
August 2020

HOPX regulates bone marrow-derived mesenchymal stromal cell fate determination via suppression of adipogenic gene pathways.

Sci Rep 2020 07 9;10(1):11345. Epub 2020 Jul 9.

Mesenchymal Stem Cell Laboratory, South Australian Health and Medical Research Institute, North Terrace, Level 5, Adelaide, SA, 5001, Australia.

Previous studies of global binding patterns identified the epigenetic factor, EZH2, as a regulator of the homeodomain-only protein homeobox (HOPX) gene expression during bone marrow stromal cell (BMSC) differentiation, suggesting a potential role for HOPX in regulating BMSC lineage specification. In the present study, we confirmed that EZH2 direct binds to the HOPX promoter region, during normal growth and osteogenic differentiation but not under adipogenic inductive conditions. HOPX gene knockdown and overexpression studies demonstrated that HOPX is a promoter of BMSC proliferation and an inhibitor of adipogenesis. However, functional studies failed to observe any affect by HOPX on BMSC osteogenic differentiation. RNA-seq analysis of HOPX overexpressing BMSC during adipogenesis, found HOPX function to be acting through suppression of adipogenic pathways associated genes such as ADIPOQ, FABP4, PLIN1 and PLIN4. These findings suggest that HOPX gene target pathways are critical factors in the regulation of fat metabolism.
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http://dx.doi.org/10.1038/s41598-020-68261-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347885PMC
July 2020

LCRF-0006, a small molecule mimetic of the N-cadherin antagonist peptide ADH-1, synergistically increases multiple myeloma response to bortezomib.

FASEB Bioadv 2020 Jun 15;2(6):339-353. Epub 2020 Jun 15.

Myeloma Research Laboratory Adelaide Medical School Faculty of Health and Medical Sciences The University of Adelaide Adelaide Australia.

N-cadherin is a homophilic cell-cell adhesion molecule that plays a critical role in maintaining vascular stability and modulating endothelial barrier permeability. Pre-clinical studies have shown that the N-cadherin antagonist peptide, ADH-1, increases the permeability of tumor-associated vasculature thereby increasing anti-cancer drug delivery to tumors and enhancing tumor response. Small molecule library screens have identified a novel compound, LCRF-0006, that is a mimetic of the classical cadherin His-Ala-Val sequence-containing region of ADH-1. Here, we evaluated the vascular permeability-enhancing and anti-cancer properties of LCRF-0006 using in vitro vascular disruption and cell apoptosis assays, and a well-established pre-clinical model (C57BL/KaLwRij/5TGM1) of the hematological cancer multiple myeloma (MM). We found that LCRF-0006 disrupted endothelial cell junctions in a rapid, transient and reversible manner, and increased vascular permeability in vitro and at sites of MM tumor in vivo. Notably, LCRF-0006 synergistically increased the in vivo anti-MM tumor response to low-dose bortezomib, a frontline anti-MM agent, leading to regression of disease in 100% of mice. Moreover, LCRF-0006 and bortezomib synergistically induced 5TGM1 MM tumor cell apoptosis in vitro. Our findings demonstrate the potential clinical utility of LCRF-0006 to significantly increase bortezomib effectiveness and enhance the depth of tumor response in patients with MM.
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http://dx.doi.org/10.1096/fba.2019-00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325588PMC
June 2020

P-Related Protein Accelerates Human Mesenchymal Stromal Cell Migration by Modulating VLA-5 Interactions with Fibronectin.

Cells 2020 04 29;9(5). Epub 2020 Apr 29.

Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9BQ, UK.

P-related protein (PZR), a Noonan and Leopard syndrome target, is a member of the transmembrane Immunoglobulin superfamily. Its cytoplasmic tail contains two immune-receptor tyrosine-based inhibitory motifs (ITIMs), implicated in adhesion-dependent signaling and regulating cell adhesion and motility. PZR promotes cell migration on the extracellular matrix (ECM) molecule, fibronectin, by interacting with SHP-2 (Src homology-2 domain-containing protein tyrosine phosphatase-2), a molecule essential for skeletal development and often mutated in Noonan and Leopard syndrome patients sharing overlapping musculoskeletal abnormalities and cardiac defects. To further explore the role of PZR, we assessed the expression of PZR and its ITIM-less isoform, PZRb, in human bone marrow mesenchymal stromal cells (hBM MSC), and its ability to facilitate adhesion to and spreading and migration on various ECM molecules. Furthermore, using siRNA knockdown, confocal microscopy, and immunoprecipitation assays, we assessed PZR and PZRb interactions with β1 integrins. PZR was the predominant isoform in hBM MSC. Migrating hBM MSCs interacted most effectively with fibronectin and required the association of PZR, but not PZRb, with the integrin, VLA-5(α5β1), leading to modulation of focal adhesion kinase phosphorylation and vinculin levels. This raises the possibility that dysregulation of PZR function may modify hBM MSC migratory behavior, potentially contributing to skeletal abnormalities.
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http://dx.doi.org/10.3390/cells9051100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290418PMC
April 2020

CMTM8 Is a Suppressor of Human Mesenchymal Stem Cell Osteogenic Differentiation and Promoter of Proliferation Via EGFR Signaling.

Stem Cells Dev 2020 07 4;29(13):823-834. Epub 2020 May 4.

South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.

Multipotent bone marrow-derived mesenchymal stem/stromal cells (BMSCs) exhibit a finite life span after ex vivo expansion leading to cellular senescence. Many factors can contribute to this. Recently, our group has identified for the first time expression of the chemokine-like factor superfamily 8 (CMTM8) gene in cultured human BMSCs. In this study, we examine the role of CMTM8 in BMSC proliferation, migration, and differentiation. Functional studies using siRNA-mediated knockdown of in human BMSCs resulted in decreased capacity to undergo proliferation and migration and an increased capacity for osteogenic differentiation in vitro. Furthermore, reduced levels led to a decrease in the epidermal growth factor receptor (EGFR) signaling pathway during BMSC proliferation and migration, respectively. Supportive studies using retroviral mediated enforced expression of in BMSC resulted in an increased capacity for proliferation and migration but a decreased osteogenic differentiation potential. Collectively, these data suggest that CMTM8 promotes BMSC proliferation and BMSC migration through the EGFR/ERK1/2 pathway. This study provides insight into novel regulatory mechanisms of human BMSC growth and cell fate determination.
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http://dx.doi.org/10.1089/scd.2020.0007DOI Listing
July 2020

Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis.

Cell Mol Life Sci 2021 Jan 13;78(1):249-270. Epub 2020 Mar 13.

Lifelong Health Theme, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.

eIF4E plays key roles in protein synthesis and tumorigenesis. It is phosphorylated by the kinases MNK1 and MNK2. Binding of MNKs to eIF4G enhances their ability to phosphorylate eIF4E. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G. These effects provide a novel mechanism by which mTORC1 signaling impairs the function of MNK2 and thereby decreases eIF4E phosphorylation. MNK2[S74A] knock-in cells show enhanced phosphorylation of eIF4E and S6K1 (i.e., increased mTORC1 signaling), enlarged cell size, and increased invasive and transformative capacities. MNK2[Ser74] phosphorylation was inversely correlated with disease progression in human prostate tumors. MNK inhibition exerted anti-proliferative effects in prostate cancer cells in vitro. These findings define a novel feedback loop whereby mTORC1 represses MNK2 activity and oncogenic signaling through eIF4E phosphorylation, allowing reciprocal regulation of these two oncogenic pathways.
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http://dx.doi.org/10.1007/s00018-020-03491-1DOI Listing
January 2021

Twist-1 is upregulated by NSD2 and contributes to tumour dissemination and an epithelial-mesenchymal transition-like gene expression signature in t(4;14)-positive multiple myeloma.

Cancer Lett 2020 04 31;475:99-108. Epub 2020 Jan 31.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia. Electronic address:

Approximately 15% of patients with multiple myeloma (MM) harbour the t(4;14) chromosomal translocation, leading to the overexpression of the histone methyltransferase NSD2. Patients with this translocation display increased tumour dissemination, accelerated disease progression and rapid relapse. Using publicly available gene expression profile data from NSD2 (n = 135) and NSD2 (n = 878) MM patients, we identified 39 epithelial-mesenchymal transition (EMT)-associated genes which are overexpressed in NSD2 MM plasma cells. In addition, our analyses identified Twist-1 as a key transcription factor upregulated in NSD2 MM patients and t(4;14)-positive cell lines. Overexpression and knockdown studies confirmed that Twist-1 is involved in driving the expression of EMT-associated genes in the human MM cell line KMS11 and promoted the migration of myeloma cell lines in vitro. Notably, Twist-1 overexpression in the mouse MM cell line 5TGM1 significantly increased tumour dissemination in an intratibial tumour model. These findings demonstrate that Twist-1, downstream of NSD2, contributes to the induction of an EMT-like signature in t(4;14)-positive MM and enhances the dissemination of MM plasma cells in vivo, which may, in part, explain the aggressive disease features associated with t(4;14)-positive MM.
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http://dx.doi.org/10.1016/j.canlet.2020.01.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829063PMC
April 2020

Fabrication of a Cartilage Patch by Fusing Hydrogel-Derived Cell Aggregates onto Electrospun Film.

Tissue Eng Part A 2020 08 19;26(15-16):863-871. Epub 2020 Mar 19.

School of Chemical Engineering and Advanced Materials, The University of Adelaide, Adelaide, Australia.

Irregular defects at sites of degenerative cartilage often accompany osteoarthritis (OA). The development of novel cell-/biomaterial-based cartilage tissue engineering methods to address these defects may provide a durable approach to hinder the development of OA. In this study, we fabricated a neocartilage patch by fusing cell aggregates onto a biodegradable nanofiber film for degenerative cartilage repair. Human mesenchymal stem/stromal cell (MSC) aggregates were prepared and induced for chondrogenesis in a thermosensitive hydrogel, poly (-isopropylacrylamide-co-acrylic acid (p(NIPAAm-AA)). Cell migration mediated the formation of cell aggregates in the thermosensitive hydrogel and led to a cell-dense hollow shell structure. The chondrocytes derived from MSC aggregates in the hydrogel were evidenced by the expression of chondrogenesis-related genes and extracellular matrices. They were fused onto an electrospun film by mechanical force and spatial confinement to generate a neo-cartilage patch. The fabricated neocartilage patches may be able to integrate into the irregular defects under compressive stresses and achieve cartilage regeneration . Impact statement The formation of human mesenchymal stem/stromal cells aggregates in thermosensitive hydrogels was mechanistically examined. These formed cell aggregates with enhanced chondrogenesis were bioengineered into a neocartilage patch for regeneration of superficial irregular cartilage defects.
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http://dx.doi.org/10.1089/ten.TEA.2019.0318DOI Listing
August 2020

GLIPR1 expression is reduced in multiple myeloma but is not a tumour suppressor in mice.

PLoS One 2020 29;15(1):e0228408. Epub 2020 Jan 29.

Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.

Multiple myeloma, a plasma cell malignancy, is a genetically heterogeneous disease and the genetic factors that contribute to its development and progression remain to be fully elucidated. The tumour suppressor gene GLIPR1 has previously been shown to be deleted in approximately 10% of myeloma patients, to inhibit the development of plasma cell tumours in ageing mice and to have reduced expression levels in the plasma cells of patients with light-chain amyloidosis, a myeloma-related malignancy. Therefore, we hypothesised that GLIPR1 may have tumour suppressor activity in multiple myeloma. In this study, we demonstrate that plasma cell expression of GLIPR1 is reduced in the majority of myeloma patients and Glipr1 expression is lost in the 5TGM1 murine myeloma cell line. However, overexpression of GLIPR1 in a human myeloma cell line did not affect cell proliferation in vitro. Similarly, re-expression of Glipr1 in 5TGM1 cells did not significantly reduce their in vitro proliferation or in vivo growth in C57BL/KaLwRij mice. In addition, using CRISPR-Cas9 genome editing, we generated C57BL/Glipr1-/- mice and showed that loss of Glipr1 in vivo did not affect normal haematopoiesis or the development of monoclonal plasma cell expansions in these mice up to one year of age. Taken together, our results suggest that GLIPR1 is unlikely to be a potent tumour suppressor in multiple myeloma. However, it remains possible that the down-regulation of GLIPR1 may cooperate with other genetic lesions to promote the development of myeloma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988976PMC
April 2020

Conditional knockout of ephrinB1 in osteogenic progenitors delays the process of endochondral ossification during fracture repair.

Bone 2020 03 19;132:115189. Epub 2019 Dec 19.

Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia. Electronic address:

The Eph receptor tyrosine kinase ligand, ephrinB1 (EfnB1) is important for correct skeletal and cartilage development, however, the role of EfnB1 in fracture repair is unknown. This study investigated the role of EfnB1 during fracture repair where EfnB1 expression increased significantly at 1 and 2 weeks post fracture in C57Bl/6 wildtype mice, coinciding with the haematoma, soft callus formation/remodelling stages, respectively. To investigate the specific role of EfnB1 within the osteogenic lineage during fracture repair, male mice with a conditional deletion of EfnB1 in the osteogenic lineage (EfnB1), driven by the Osterix (Osx) promoter, and their male Osx:Cre counterparts were subject to a femoral fracture with internal fixation. Two weeks post fracture micro computed tomography (μCT) analysis revealed that EfnB1 mice displayed a significant decrease in bone volume relative to tissue volume within the fracture callus. This was attributed to an alteration in the distribution of osteoclasts within the fracture site, a significant elevation in cartilaginous tissue and reduction in the osteoprogenitor population and calcein labelled bone within the fracture site of EfnB1 mice. Supportive in vitro studies demonstrated that under osteogenic conditions, cultured EfnB1 stromal cells derived from the 2 week fracture site exhibited a reduced capacity to produce mineral and decreased expression of the osteogenic gene, Osterix, when compared to Osx:Cre controls. These findings suggest that the loss of EfnB1 delays the fracture repair process. The present study confirmed that EFNB1 activation in human BMSC, following stimulation with soluble-EphB2 resulted in de-phosphorylation of TAZ, demonstrating similarities in EfnB1 signalling between human and mouse stromal populations. Overall, the present study provides evidence that loss of EfnB1 in the osteo/chondrogenic lineages delays the soft callus formation/remodelling stages of the fracture repair process.
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http://dx.doi.org/10.1016/j.bone.2019.115189DOI Listing
March 2020

Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo.

Neoplasia 2019 08 24;21(8):777-787. Epub 2019 Jun 24.

Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide, 5005; Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, PO Box 11060, Adelaide, 5001; Centre for Cancer Biology, University of South Australia and SA Pathology, PO Box 2471, Adelaide, 5001. Electronic address:

Multiple myeloma is a fatal plasma cell malignancy that is reliant on the bone marrow microenvironment. The bone marrow is comprised of numerous cells of mesenchymal and hemopoietic origin. Of these, macrophages have been implicated to play a role in myeloma disease progression, angiogenesis, and drug resistance; however, the role of macrophages in myeloma disease establishment remains unknown. In this study, the antimyeloma efficacy of clodronate-liposome treatment, which globally and transiently depletes macrophages, was evaluated in the well-established C57BL/KaLwRijHsd murine model of myeloma. Our studies show, for the first time, that clodronate-liposome pretreatment abrogates myeloma tumor development in vivo. Clodronate-liposome administration resulted in depletion of CD169 bone marrow-resident macrophages. Flow cytometric analysis revealed that clodronate-liposome pretreatment impaired myeloma plasma cell homing and retention within the bone marrow 24 hours postmyeloma plasma cell inoculation. This was attributed in part to decreased levels of macrophage-derived insulin-like growth factor 1. Moreover, a single dose of clodronate-liposome led to a significant reduction in myeloma tumor burden in KaLwRij mice with established disease. Collectively, these findings support a role for CD169-expressing bone marrow-resident macrophages in myeloma disease establishment and progression and demonstrate the potential of targeting macrophages as a therapy for myeloma patients.
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http://dx.doi.org/10.1016/j.neo.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593350PMC
August 2019

A niche-dependent myeloid transcriptome signature defines dormant myeloma cells.

Blood 2019 07 25;134(1):30-43. Epub 2019 Apr 25.

Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.

The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.
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http://dx.doi.org/10.1182/blood.2018880930DOI Listing
July 2019

Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination.

Epigenetics Chromatin 2019 01 3;12(1). Epub 2019 Jan 3.

Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, 5000, Australia.

Background: The 5 hydroxymethylation (5hmC) mark and TET DNA dioxygenases play a pivotal role in embryonic stem cell differentiation and animal development. However, very little is known about TET enzymes in lineage determination of human bone marrow-derived mesenchymal stem/stromal cells (BMSC). We examined the function of all three TET DNA dioxygenases, responsible for DNA hydroxymethylation, in human BMSC cell osteogenic and adipogenic differentiation.

Results: We used siRNA knockdown and retroviral mediated enforced expression of TET molecules and discovered TET1 to be a repressor of both osteogenesis and adipogenesis. TET1 was found to recruit the co-repressor proteins, SIN3A and the histone lysine methyltransferase, EZH2 to osteogenic genes. Conversely, TET2 was found to be a promoter of both osteogenesis and adipogenesis. The data showed that TET2 was directly responsible for 5hmC levels on osteogenic and adipogenic lineage-associated genes, whereas TET1 also played a role in this process. Interestingly, TET3 showed no functional effect in BMSC osteo-/adipogenic differentiation. Finally, in a mouse model of ovariectomy-induced osteoporosis, the numbers of clonogenic BMSC were dramatically diminished corresponding to lower trabecular bone volume and reduced levels of TET1, TET2 and 5hmC.

Conclusion: The present study has discovered an epigenetic mechanism mediated through changes in DNA hydroxymethylation status regulating the activation of key genes involved in the lineage determination of skeletal stem cells, which may have implications in BMSC function during normal bone regulation. Targeting TET molecules or their downstream targets may offer new therapeutic strategies to help prevent bone loss and repair following trauma or disease.
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http://dx.doi.org/10.1186/s13072-018-0247-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317244PMC
January 2019

Using genomics to better define high-risk MGUS/SMM patients.

Oncotarget 2018 Nov 27;9(93):36549-36550. Epub 2018 Nov 27.

Andrew C.W. Zannettino: Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia; Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.

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http://dx.doi.org/10.18632/oncotarget.26390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290965PMC
November 2018

Loss of EfnB1 in the osteogenic lineage compromises their capacity to support hematopoietic stem/progenitor cell maintenance.

Exp Hematol 2019 01 13;69:43-53. Epub 2018 Oct 13.

Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia; Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia. Electronic address:

The bone marrow stromal microenvironment contributes to the maintenance and function of hematopoietic stem/progenitor cells (HSPCs). The Eph receptor tyrosine kinase family members have been implicated in bone homeostasis and stromal support of HSPCs. The present study examined the influence of EfnB1-expressing osteogenic lineage on HSPC function. Mice with conditional deletion of EfnB1 in the osteogenic lineage (EfnB1), driven by the Osterix promoter, exhibited a reduced prevalence of osteogenic progenitors and osteoblasts, correlating to lower numbers of HSPCs compared with Osx:Cre mice. Long-term culture-initiating cell (LTC-IC) assays confirmed that the loss of EfnB1 within bone cells hindered HSPC function, with a significant reduction in colony formation in EfnB1 mice compared with Osx:Cre mice. Human studies confirmed that activation of EPHB2 on CD34 HSPCs via EFNB1-Fc stimulation enhanced myeloid/erythroid colony formation, whereas functional blocking of either EPHB1 or EPHB2 inhibited the maintenance of LTC-ICs. Moreover, EFNB1 reverse signaling in human and mouse stromal cells was found to be required for the activation of the HSPC-promoting factor CXCL12. Collectively, the results of this study confirm that EfnB1 contributes to the stromal support of HSPC function and maintenance and may be an important factor in regulating the HSPC niche.
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http://dx.doi.org/10.1016/j.exphem.2018.10.004DOI Listing
January 2019
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