Publications
365 results found
Godwin JW, Pinto AR, Rosenthal NA, 2017, Chasing the recipe for a pro-regenerative immune system, Seminars in Cell and Developmental Biology, Vol: 61, Pages: 71-79, ISSN: 1084-9521
Identification of the key ingredients and essential processes required to achieve perfect tissue regeneration in humans has so far remained elusive. Injury in vertebrates induces an obligatory wound response that will precede or overlap any regeneration specific program or scarring outcome. This process shapes the cellular and molecular landscape of the tissue, influencing the success of endogenous repair pathways or for potential clinical intervention. The involvement of immune cells is also required for aspects of development extending beyond the initial inflammatory phase of wounding. It has now become clear from amphibian, fish and mammalian models of tissue injury that the type of immune response and the profile of immune cells attending the site of injury can act as the gatekeepers that determine wound repair quality. The heterogeneity among innate and adaptive immune cell populations, along with the developmental origin of these cells, form key ingredients affecting the potential for downstream repair and the suppression of fibrosis. Cell-to-cell interactions between immune cells, such as macrophages and T cells, with stem cells and mesenchymal cells are critically important for shaping this process and these exchanges, are in turn influenced by the type of injury, tissue location and developmental stage of the organism. Developmentally, mouse cardiac regeneration is restricted to early stages of postnatal life where the balance of innate to adaptive immune cells may be poised towards regeneration. In the injured adult mouse liver, specific macrophage subsets improve repair while other bone marrow derived cells can exacerbate injury. Other studies using genetically diverse mice have shown enhanced regeneration in certain strains, restricted to specific tissues. This enhanced repair is linked with expression of genes such as Insulin-like Growth Factor- 1 (IGF-1) and activin (Act 1), that both play important roles in shaping the immune system. Immune cells are
Furtado MB, Costa MW, Rosenthal NA, 2016, The cardiac fibroblast: Origin, identity and role in homeostasis and disease, DIFFERENTIATION, Vol: 92, Pages: 93-101, ISSN: 0301-4681
Gallego Colon EJ, Villalba M, Tonkin J, et al., 2016, Intravenous delivery of adeno-associated virus 9-encoded IGF-1Ea propeptide improves post-infarct cardiac remodelling, npj Regenerative Medicine, Vol: 1, ISSN: 2057-3995
The insulin-like growth factor Ea propeptide (IGF-1Ea) is a powerful enhancer of cardiac muscle growth and regeneration, also blocking age-related atrophy and beneficial in multiple skeletal muscle diseases. The therapeutic potential of IGF-1Ea compared with mature IGF-1 derives from its local action in the area of synthesis. We have developed an adeno-associated virus (AAV) vector for IGF-1Ea delivery to the heart to treat mice after myocardial infarction and examine the reparative effects of local IGF-1Ea production on left ventricular remodelling. A cardiotropic AAV9 vector carrying a cardiomyocyte-specific IGF-1Ea-luciferase bi-cistronic gene expression cassette (AAV9.IGF-1Ea) was administered intravenously to infarcted mice, 5 h after ischemia followed by reperfusion (I/R), as a model of myocardial infarction. Virally encoded IGF-1Ea in the heart improved global left ventricular function and remodelling, as measured by wall motion and thickness, 28 days after delivery, with higher viral titers yielding better improvement. The present study demonstrates that single intravenous AAV9-mediated IGF-1Ea Gene Therapy represents a tissue-targeted therapeutic approach to prevent the adverse remodelling after myocardial infarct.
Rosenthal N, Badylak S, 2016, Regenerative medicine: today's discoveries informing the future of medical practice, npj Regenerative Medicine, Vol: 1, ISSN: 2057-3995
Pinto AR, Ilinykh A, Ivey MJ, et al., 2016, Revisiting cardiac cellular composition, Circulation Research, Vol: 118, Pages: 400-409, ISSN: 0009-7330
Rationale:Accurate knowledge of the cellular composition of the heart is essential to fully understand the changes that occur during pathogenesis and to devise strategies for tissue engineering and regeneration.Objective:To examine the relative frequency of cardiac endothelial cells, hematopoietic-derived cells, and fibroblasts in the mouse and human heart.Methods and Results:Using a combination of genetic tools and cellular markers, we examined the occurrence of the most prominent cell types in the adult mouse heart. Immunohistochemistry revealed that endothelial cells constitute >60%, hematopoietic-derived cells 5% to 10%, and fibroblasts <20% of the nonmyocytes in the heart. A refined cell isolation protocol and an improved flow cytometry approach provided an independent means of determining the relative abundance of nonmyocytes. High-dimensional analysis and unsupervised clustering of cell populations confirmed that endothelial cells are the most abundant cell population. Interestingly, fibroblast numbers are smaller than previously estimated, and 2 commonly assigned fibroblast markers, Sca-1 and CD90, under-represent fibroblast numbers. We also describe an alternative fibroblast surface marker that more accurately identifies the resident cardiac fibroblast population.Conclusions:This new perspective on the abundance of different cell types in the heart demonstrates that fibroblasts comprise a relatively minor population. By contrast, endothelial cells constitute the majority of noncardiomyocytes and are likely to play a greater role in physiological function and response to injury than previously appreciated.
Kaloff C, Anastassiadis K, Ayadi A, et al., 2016, Genome wide conditional mouse knockout resources, Drug Discovery Today: Disease Models, Vol: 20, Pages: 3-12
The International Knockout Mouse Consortium (IKMC) developed high throughput gene trapping and gene targeting pipelines that produced mostly conditional mutations of more than 18,500 genes in C57BL/6N mouse embryonic stem (ES) cells which have been archived and are freely available to the research community as a frozen resource. From this unprecedented resource more than 6000 mutant mouse strains have been generated by the IKMC in collaboration with the International Mouse Phenotyping Consortium (IMPC). In addition, a cre-driver resource was established including 250 C57BL/6 cre-inducible mouse strains. Complementing the cre-driver resource, a collection comprising 27 rAAVs expressing cre in a tissue-specific manner has also been produced. All resources are easily accessible from the IKMC/IMPC web portal (www.mousephenotype.org). The IKMC/IMPC resource is a standardized reference library of mouse models with defined genetic backgrounds enabling the analysis of gene-disease associations in mice of different genetic makeup and should therefore have a major impact on biomedical research.
Furtado MB, Nim HT, Boyd SE, et al., 2016, View from the heart: cardiac fibroblasts in development, scarring and regeneration, DEVELOPMENT, Vol: 143, Pages: 387-397, ISSN: 0950-1991
- Author Web Link
- Cite
- Citations: 104
Tabibian-Keissar H, Hazanov L, Schiby G, et al., 2016, Aging affects B-cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 46, Pages: 480-492, ISSN: 0014-2980
- Author Web Link
- Cite
- Citations: 46
Sattler S, Rosenthal N, 2016, The neonate versus adult mammalian immune system in cardiac repair and regeneration, BBA - Molecular Cell Research, Vol: 1863, Pages: 1813-1821, ISSN: 0167-4889
The immune system is a crucial player in tissue homeostasis and woundhealing. A sophisticated cascade of events triggered upon injury ensuresprotection from infection and initiates and orchestrates healing. While theneonatal mammal can readily regenerate damaged tissues, adult regenerativecapacity is limited to specific tissue types, and in organs such as the heart,adult wound healing results in fibrotic repair and loss of function. Growingevidence suggests that the immune system greatly influences the balancebetween regeneration and fibrotic repair. The neonate mammalian immunesystem has impaired pro-inflammatory function, is prone to T-helper type 2responses and has an immature adaptive immune system skewed towardsregulatory T cells. While these characteristics make infants susceptible toinfection and prone to allergies, it may also provide an immunologicalenvironment permissive of regeneration.In this review we will give a comprehensive overview of the immune cellsinvolved in healing and regeneration of the heart and explore differencesbetween the adult and neonate immune system that may explain differencesin regenerative ability.
Furtado MB, Wilmanns JC, Chandran A, et al., 2016, A novel conditional mouse model for Nkx2-5 reveals transcriptional regulation of cardiac ion channels, DIFFERENTIATION, Vol: 91, Pages: 29-41, ISSN: 0301-4681
Kennedy-Lydon T, Rosenthal N, 2015, Cardiac regeneration: epicardial mediated repair, Proceedings of the Royal Society B: Biological Sciences, Vol: 282, ISSN: 0962-8452
The hearts of lower vertebrates such as fish and salamanders display scarless regeneration following injury, although this feature is lost in adult mammals. The remarkable capacity of the neonatal mammalian heart to regenerate suggests that the underlying machinery required for the regenerative process is evolutionarily retained. Recent studies highlight the epicardial covering of the heart as an important source of the signalling factors required for the repair process. The developing epicardium is also a major source of cardiac fibroblasts, smooth muscle, endothelial cells and stem cells. Here, we examine animal models that are capable of scarless regeneration, the role of the epicardium as a source of cells, signalling mechanisms implicated in the regenerative process and how these mechanisms influence cardiomyocyte proliferation. We also discuss recent advances in cardiac stem cell research and potential therapeutic targets arising from these studies.
Nim HT, Furtado MB, Costa MW, et al., 2015, CARFMAP: A Curated Pathway Map of Cardiac Fibroblasts, PLOS One, Vol: 10, ISSN: 1932-6203
The adult mammalian heart contains multiple cell types that work in unison under tightly regulated conditions to maintain homeostasis. Cardiac fibroblasts are a significant and unique population of non-muscle cells in the heart that have recently gained substantial interest in the cardiac biology community. To better understand this renaissance cell, it is essential to systematically survey what has been known in the literature about the cellular and molecular processes involved. We have built CARFMAP (http://visionet.erc.monash.edu.au/CARFMAP), an interactive cardiac fibroblast pathway map derived from the biomedical literature using a software-assisted manual data collection approach. CARFMAP is an information-rich interactive tool that enables cardiac biologists to explore the large body of literature in various creative ways. There is surprisingly little overlap between the cardiac fibroblast pathway map, a foreskin fibroblast pathway map, and a whole mouse organism signalling pathway map from the REACTOME database. Among the use cases of CARFMAP is a common task in our cardiac biology laboratory of identifying new genes that are (1) relevant to cardiac literature, and (2) differentially regulated in high-throughput assays. From the expression profiles of mouse cardiac and tail fibroblasts, we employed CARFMAP to characterise cardiac fibroblast pathways. Using CARFMAP in conjunction with transcriptomic data, we generated a stringent list of six genes that would not have been singled out using bioinformatics analyses alone. Experimental validation showed that five genes (Mmp3, Il6, Edn1, Pdgfc and Fgf10) are differentially regulated in the cardiac fibroblast. CARFMAP is a powerful tool for systems analyses of cardiac fibroblasts, facilitating systems-level cardiovascular research.
Levine RA, Hagege AA, Judge DP, et al., 2015, Mitral valve disease morphology and mechanisms, NATURE REVIEWS CARDIOLOGY, Vol: 12, Pages: 689-710, ISSN: 1759-5002
- Author Web Link
- Cite
- Citations: 221
Gallego Colon E, Sampson RD, Sattler S, et al., 2015, Cardiac-restricted IGF-1Ea overexpression reduces the early accumulation of inflammatory myeloid cells and mediates expression of extracellular matrix remodelling genes after myocardial infarction, Mediators of Inflammation, Vol: 2015, ISSN: 1466-1861
Strategies to limit damage and improve repair after myocardial infarct remain a major therapeutic goal in cardiology. Our previous studies have shown that constitutive expression of a locally acting insulin-like growth factor-1 Ea (IGF-1Ea) propeptide promotes functional restoration after cardiac injury associated with decreased scar formation. In the current study, we investigated the underlying molecular and cellular mechanisms behind the enhanced functional recovery. We observed improved cardiac function in mice overexpressing cardiac-specific IGF-1Ea as early as day 7 after myocardial infarction. Analysis of gene transcription revealed that supplemental IGF-1Ea regulated expression of key metalloproteinases (MMP-2 and MMP-9), their inhibitors (TIMP-1 and TIMP-2), and collagen types (Col 1α1 and Col 1α3) in the first week after injury. Infiltration of inflammatory cells, which direct the remodelling process, was also altered; in particular there was a notable reduction in inflammatory Ly6C+ monocytes at day 3 and an increase in anti-inflammatory CD206+ macrophages at day 7. Taken together, these results indicate that the IGF-1Ea transgene shifts the balance of innate immune cell populations early after infarction, favouring a reduction in inflammatory myeloid cells. This correlates with reduced extracellular matrix remodelling and changes in collagen composition that may confer enhanced scar elasticity and improved cardiac function.
Otte EA, Pinto AR, Rosenthal NA, et al., 2015, The Impact of Heterotypic Cell Communication Between MSCs and Mature Cells, 4th TERMIS World Congress, Publisher: MARY ANN LIEBERT, INC, Pages: S46-S47, ISSN: 1937-3341
Tonkin J, Temmerman L, Sampson RD, et al., 2015, Monocyte/Macrophage-derived IGF-1 Orchestrates Murine Skeletal Muscle Regeneration and Modulates Autocrine Polarization, MOLECULAR THERAPY, Vol: 23, Pages: 1189-1200, ISSN: 1525-0016
- Author Web Link
- Open Access Link
- Cite
- Citations: 203
Nim HT, Furtado MB, Costa MW, et al., 2015, VISIONET: intuitive visualisation of overlapping transcription factor networks, with applications in cardiogenic gene discovery, BMC Bioinformatics, Vol: 16, ISSN: 1471-2105
BackgroundExisting de novo software platforms have largely overlooked a valuable resource, the expertise of the intended biologist users. Typical data representations such as long gene lists, or highly dense and overlapping transcription factor networks often hinder biologists from relating these results to their expertise.ResultsVISIONET, a streamlined visualisation tool built from experimental needs, enables biologists to transform large and dense overlapping transcription factor networks into sparse human-readable graphs via numerically filtering. The VISIONET interface allows users without a computing background to interactively explore and filter their data, and empowers them to apply their specialist knowledge on far more complex and substantial data sets than is currently possible. Applying VISIONET to the Tbx20-Gata4 transcription factor network led to the discovery and validation of Aldh1a2, an essential developmental gene associated with various important cardiac disorders, as a healthy adult cardiac fibroblast gene co-regulated by cardiogenic transcription factors Gata4 and Tbx20.ConclusionsWe demonstrate with experimental validations the utility of VISIONET for expertise-driven gene discovery that opens new experimental directions that would not otherwise have been identified.
Tonkin J, Rosenthal N, 2015, One Small Step for Muscle: A New Micropeptide Regulates Performance, CELL METABOLISM, Vol: 21, Pages: 515-516, ISSN: 1550-4131
- Author Web Link
- Cite
- Citations: 11
Cotton LM, Meilak ML, Templeton T, et al., 2015, Utilising the resources of the International Knockout Mouse Consortium: the Australian experience, MAMMALIAN GENOME, Vol: 26, Pages: 142-153, ISSN: 0938-8990
- Author Web Link
- Cite
- Citations: 13
Rosenthal N, 2015, Prologue, Success Strategies From Women in STEM: A Portable Mentor, Pages: liii-lvii
Nim HT, Boyd SE, Rosenthal NA, 2015, Systems approaches in integrative cardiac biology: Illustrations from cardiac heterocellular signalling studies, PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY, Vol: 117, Pages: 69-77, ISSN: 0079-6107
- Author Web Link
- Cite
- Citations: 5
Furtado MB, Nim HT, Gould JA, et al., 2014, Microarray profiling to analyse adult cardiac fibroblast identity, Genomics Data, Vol: 2, Pages: 345-350, ISSN: 2213-5960
Heart failure is one of the leading causes of death worldwide [1-4]. Current therapeutic strategies are inefficient and cannot cure this chronic and debilitating condition [5]. Ultimately, heart transplants are required for patient survival, but donor organs are scarce in availability and only prolong the life-span of patients for a limited time. Fibrosis is one of the main pathological features of heart failure [6,7], caused by inappropriate stimulation of fibroblasts and excessive extracellular matrix production. Therefore, an in-depth understanding of the cardiac fibroblast is essential to underpin effective therapeutic treatments for heart failure [5]. Fibroblasts in general have been an underappreciated cell type, regarded as relatively inert and providing only basic functionality; they are usually referred to as the 'biological glue' of all tissues in the body. However, more recent literature suggests that they actively participate in organ homeostasis and disease [7,8]. We have recently uncovered a unique molecular identity for fibroblasts isolated from the heart [9], expressing a set of cardiogenic transcription factors that have been previously associated with cardiomyocyte ontogenesis. This signature suggests that cardiac fibroblasts may be ideal for use in stem cell replacement therapies, as they may retain the memory of where they derive from embryologically. Our data also revealed that about 90% of fibroblasts from both tail and heart origins share a cell surface signature that has previously been described for mesenchymal stem cells (MSCs), raising the possibility that fibroblasts and MSCs may in fact be the same cell type. Thus, our findings carry profound implications for the field of regenerative medicine. Here, we describe detailed methodology and quality controls related to the gene expression profiling of cardiac fibroblasts, deposited at the Gene Expression Omnibus (GEO) under the accession number GSE50531. We also provide the R code to ea
Godwin J, Kuraitis D, Rosenthal N, 2014, Extracellular matrix considerations for scar-free repair and regeneration: Insights from regenerative diversity among vertebrates, INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, Vol: 56, Pages: 47-55, ISSN: 1357-2725
- Author Web Link
- Cite
- Citations: 50
Rosenthal N, Grounds MD, 2014, Untitled, INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, Vol: 56, Pages: 2-3, ISSN: 1357-2725
- Author Web Link
- Cite
- Citations: 1
Pinto AR, Godwin JW, Rosenthal NA, 2014, Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation, STEM CELL RESEARCH, Vol: 13, Pages: 705-714, ISSN: 1873-5061
- Author Web Link
- Cite
- Citations: 65
Bilbao D, Luciani L, Johannesson B, et al., 2014, Insulin‐like growth factor‐1 stimulates regulatory T cells and suppresses autoimmune disease, EMBO Molecular Medicine, Vol: 6, Pages: 1423-1435, ISSN: 1757-4676
The recent precipitous rise in autoimmune diseases is placing an increasing clinical and economic burden on health systems worldwide. Current therapies are only moderately efficacious, often coupled with adverse side effects. Here, we show that recombinant human insulin‐like growth factor‐1 (rhIGF‐1) stimulates proliferation of both human and mouse regulatory T (Treg) cells in vitro and when delivered systemically via continuous minipump, it halts autoimmune disease progression in mouse models of type 1 diabetes (STZ and NOD) and multiple sclerosis (EAE) in vivo. rhIGF‐1 administration increased Treg cells in affected tissues, maintaining their suppressive properties. Genetically, ablation of the IGF‐1 receptor specifically on Treg cell populations abrogated the beneficial effects of rhIGF‐1 administration on the progression of multiple sclerotic symptoms in the EAE model, establishing a direct effect of IGF‐1 on Treg cell proliferation. These results establish systemically delivered rhIGF‐1 as a specific, effective stimulator of Treg cell action, underscoring the clinical feasibility of manipulating natural tolerance mechanisms to suppress autoimmune disease.
Molawi K, Wolf Y, Kandalla PK, et al., 2014, Progressive replacement of embryo-derived cardiac macrophages with age, Journal of Experimental Medicine, Vol: 211, Pages: 2151-2158, ISSN: 0022-1007
Cardiac macrophages (cM) are critical for early postnatal heart regeneration and fibrotic repair in the adult heart, but their origins and cellular dynamics during postnatal develop-ment have not been well characterized. Tissue macrophages can be derived from embryonic progenitors or from monocytes during inflammation. We report that within the first weeks after birth, the embryo-derived population of resident CX3CR1+ cM diversifies into MHCII+ and MHCII cells. Genetic fate mapping demonstrated that cM derived from CX3CR1+ embryonic progenitors persisted into adulthood but the initially high contribution to resident cM declined after birth. Consistent with this, the early significant prolifera-tion rate of resident cM decreased with age upon diversification into subpopulations. Bone marrow (BM) reconstitution experiments showed monocyte-dependent quantitative replacement of all cM populations. Furthermore, parabiotic mice and BM chimeras of nonirradiated recipient mice revealed a slow but significant donor contribution to cM. Together, our observations indicate that in the heart, embryo-derived cM show declining self-renewal with age and are progressively substituted by monocyte-derived macrophages, even in the absence of inflammation.
Forbes SJ, Rosenthal N, 2014, Preparing the ground for tissue regeneration: from mechanism to therapy, NATURE BIOTECHNOLOGY, Vol: 32, Pages: 857-869, ISSN: 1087-0156
Johannesson B, Sattler S, Semenova E, et al., 2014, Insulin-like growth factor-1 induces regulatory T cell-mediated suppression of allergic contact dermatitis in mice, DISEASE MODELS & MECHANISMS, Vol: 7, Pages: 977-985, ISSN: 1754-8403
- Author Web Link
- Open Access Link
- Cite
- Citations: 30
Forbes SJ, Rosenthal N, 2014, Preparing the ground for tissue regeneration: from mechanism to therapy, NATURE MEDICINE, Vol: 20, Pages: 857-869, ISSN: 1078-8956
- Author Web Link
- Cite
- Citations: 376
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.