Shinji Makino

Shinji Makino
Keio University | Keidai

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80
Publications
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Publications

Publications (80)
Article
Aims During heart failure, the levels of circulatory heat shock protein family D member 1 (HSP60) increase. However, its underlying mechanism is still unknown. The apical domain of heat shock protein family D member 1 (HSPD1) is conserved throughout evolution. We found a point mutation in HSPD1 in a familial dilated cardiomyopathy (DCM) patient. A...
Article
Full-text available
Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of the patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated...
Article
Full-text available
Versican is an evolutionary conserved extracellular matrix proteoglycan, and versican expression loss in mice results in embryonic lethality owing to cardiovascular defects. However, the in utero development of mammals limits our understanding of the precise role of versican during cardiovascular development. Therefore, the use of evolutionarily di...
Preprint
Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of the patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated...
Article
Full-text available
Fat storage-inducing transmembrane proteins 1 and 2 (FITM1 and FITM2, respectively) are transmembrane endoplasmic/sarcoplasmic reticulum proteins involved in lipid droplet formation. The physiological functions of FITM1 have only been reported in skeletal muscle, while those of FITM2 were analyzed using genetically engineered mice. However, their r...
Article
Hypertrophic cardiomyopathy (HCM) is an extremely heterogeneous genetic disease that affects the left ventricle (LV) and has a varied clinical course and phenotypic expression. Here, we report a case of two sisters with HCM who developed a massive refractory left atrial appendage (LAA) thrombus and recurrent embolism. The older sister, who was at a...
Article
Full-text available
Background: Cell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved. The gene-body regions (GBRs) of some cardiomyocyte (CM)-specific genes are long and highly hypomethylated in CMs. To explore the...
Article
The stroma provides a microenvironment that regulates tumor cell behavior. The extracellular matrix has long been recognized to be important in tumor cell behavior, and previous studies have revealed the impact of individual matrix molecules on tumor progression. Although several reports have highlighted some central roles of tumor cell-expressed v...
Article
Introduction: Despite the recent advance of genetic studies, genetic causes of hereditary dilated cardiomyopathy (DCM) are still unknown in most cases. Heat shock protein 60 (Hsp60) is a well-known chaperonin, responsible for correct folding and transportation of cytoplasmic protein to mitochondria. This study is aimed to investigate whether dysfun...
Article
Full-text available
Background Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic–environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; how...
Data
Full-text available
We have isolated a cardiomyogenic cell line (CMG) from murine bone marrow stromal cells. Stromal cells were immortalized, treated with 5- azacytidine, and spontaneously beating cells were repeatedly screened. The cells showed a fibroblast-like morphology, but the morphology changed after 5-azacytidine treatment in -30% of the cells; they connected...
Article
Purpose: To determine the function of versican (Vcan) in the cardiovascular system in vivo, we generated the versican conditional knockout mice, in which the Vcan gene was selectively ablated in vascular smooth muscle cells (SMCs). Versican is a large secreted chondroitin sulfate proteoglycan, which is important for cardiac development, and is also...
Article
MicroRNAs (miRNAs) play a pivotal role during embryonic development and are required for proper organogenesis, including hematopoiesis. Recent studies suggest that, in the early mesoderm, there is an interaction between the hematopoietic and cardiac lineages. However, whether miRNAs can affect other lineages remains unknown. Therefore, we investiga...
Article
The genetic basis of most congenital heart defects (CHDs), especially non-syndromic and non-familial conditions, remains largely unknown. DNA samples were collected from immortalized cell lines and original genomes of 256 non-syndromic, non-familial patients with cardiac outflow tract (OFT) defects. Genes encoding NKX2.5, GATA4, GATA6, MEF2C, and I...
Article
Full-text available
Musashi (Msi) is an evolutionarily conserved gene family of RNA-binding proteins (RBPs) that is preferentially expressed in the nervous system. The first member of the Msi family was identified in Drosophila. Drosophila Msi plays an important role in regulating asymmetric cell division of the sensory organ precursor cells. The mammalian orthologs,...
Article
The efficient induction of cardiomyocyte differentiation from embryonic stem (ES) cells is crucial for cardiac regenerative medicine. Although Wnts play important roles in cardiac development, complex questions remain as to when, how and what types of Wnts are involved in cardiogenesis. We found that Wnt2 was strongly up-regulated during cardiomyoc...
Article
We recently demonstrated that primitive neural crest-derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, we examined the migration and differentiation potential of these cells o...
Article
Full-text available
After skeletal muscle injury, neutrophils, monocytes, and macrophages infiltrate the damaged area; this is followed by rapid proliferation of myoblasts derived from muscle stem cells (also called satellite cells). Although it is known that inflammation triggers skeletal muscle regeneration, the underlying molecular mechanisms remain incompletely un...
Chapter
Although heart transplantation is the ultimate therapy for severe heart failure, it is not widely used owing to the inadequate supply of donor hearts. Therefore, cell-based therapies for the prevention or treatment of cardiac dysfunction have attracted significant interest. Since we first reported (in 1999) that bone marrow (BM) mesenchymal stem ce...
Article
Background: The ras-related small G-protein Rad was originally identified from skeletal muscle of patients with type 2 diabetes mellitus. We have recently reported that Rad plays a critical role in generating arrhythmias. The study was aimed to elucidate the role of Rad in intracellular calcium homeostasis. Methods and Results: We developed the tra...
Article
Mouse embryonic fibroblasts (MEFs) are the most commonly used feeder cells for pluripotent stem cells. However, autogeneic feeder (AF) cells have several advantages such as no xenogeneic risks and reduced costs. In this report, we demonstrate that common marmoset embryonic stem (cmES) cells can be maintained on common marmoset AF (cmAF) cells. Thes...
Data
Genotype Distributions of Embryos from IP3R1+/−-IP3R2−/− Intercrosses. (0.03 MB DOC)
Data
The ultrastructures of the subcellular organelles of the IP3R1−/−-IP3R2−/− mice are comparable with those of the IP3R1+/−-IP3R2−/− mice. Scale bars, 1 µm. g, golgi; m, mitochondrion; mf, myofilament; n, nucleus; rer, rough endoplasmic reticulum; sr, sarcoplasmic reticulum. (1.74 MB TIF)
Data
Expression of site-specific markers in embryonic hearts. Whole-mount in situ hybridization images of the left- or right-side of the hearts of E9.5 IP3R1+/−-IP3R2−/- (upper panels) and IP3R1−/−-IP3R2−/− (lower panels) embryos. The expression patterns of Nkx2.5, MLC2a, and MLC2v (earliest markers of the embryonic heart), and of Hand2, Hand1 and Hrt2...
Data
Cross-sections of E9.5 placentas from IP3R1−/−-IP3R2+/− (upper panels), IP3R1+/−-IP3R2−/− (middle panels) and IP3R1−/−-IP3R2−/− (lower panels) mutant mice. The widths of the labyrinth area indicated in parentheses. Higher-magnification images of the boxed areas are shown in the right panels. Scale bars, 0.5 mm. The graph shows quantification of the...
Data
The percentages of cells with nuclear translocation of NFATc1 in the IP3R1−/−-IP3R2−/− hearts (white bars) are significantly lower than those in the IP3R1+/−-IP3R2−/− hearts (black bars) at E9.5 to E10.0 (*P<0.01, n = 3). Error bars indicate standard deviations. (2.97 MB TIF)
Data
Atrioventricular regurgitation in the zebrafish hearts treated with DMSO (top), calcineurin inhibitor, cyclosporine A, (middle) and IP3R inhibitor, 2APB, (bottom). (0.32 MB MOV)
Article
Full-text available
Inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ release channels that regulate various vital processes. Although the ryanodine receptor type 2, another type of intracellular Ca2+ release channel, has been shown to play a role in embryonic cardiomyocytes, the functions of the IP3Rs in cardiogenesis remain unclear. We...
Article
The size and morphology of organs are largely determined by a genetic program. However in some cases, an epigenetic mechanism influences the process of organ development. Particularly, epigenetic factors such as hemodynamic stress and blood pressure affect the morphogenesis of cardiac chambers and valves. Here, we report that the epigenetic influen...
Article
Full-text available
The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart....
Article
Full-text available
Several applications of pluripotent stem cell (PSC)-derived cardiomyocytes require elimination of undifferentiated cells. A major limitation for cardiomyocyte purification is the lack of easy and specific cell marking techniques. We found that a fluorescent dye that labels mitochondria, tetramethylrhodamine methyl ester perchlorate, could be used t...
Article
Myocardial cell sheets (MCS) are a potentially valuable tool for tissue engineering aimed at heart regeneration. Several methods have recently been established for the fabrication of MCS. However, the lack of a sufficient blood supply has inhibited functional recovery of the MCS. To address this challenge, we combined MCS transplantation with oment...
Article
Our studies revealed that dissociated cells from medaka (the fresh-water fish, Oryzias latipes ) blastula-stage embryos differentiate into many rhythmically contracting cells when incubated with a conditioned medium from a cell line. Analyses of these cells by immunostaining, electron microscopy, expression of marker genes, action potential recordi...
Article
Background: We have recently reported that the ras-related small G-protein Rad plays a critical role in generating arrhythmias via regulation of L-type Ca ²⁺ channel. However, it has remained unclear whether or not the mechanism for its arrhythmogenesis is attributed only to L-type Ca ²⁺ channel activity. This study was designed to demonstrate the...
Article
Inhalation of hydrogen (H(2)) gas has been demonstrated to limit the infarct volume of brain and liver by reducing ischemia-reperfusion injury in rodents. When translated into clinical practice, this therapy must be most frequently applied in the treatment of patients with acute myocardial infarction, since angioplastic recanalization of infarct-re...
Article
Common marmoset monkeys have recently attracted much attention as a primate research model, and are preferred to rhesus and cynomolgus monkeys due to their small bodies, easy handling and efficient breeding. We recently reported the establishment of common marmoset embryonic stem cell (CMESC) lines that could differentiate into three germ layers. H...
Chapter
IntroductionBone marrow mesenchymal marrow stem cells as a source of cardiomyocytesMethod of establishing bone-marrow-derived cardiomyocytesRegenerated cardiomyocytes display a fetal ventricular phenotypeDevelopmental stage of undifferentiated and differentiated cardiomyogenic cellsSerial changes in action potential shape in cardiomyogenic cells si...
Article
Background : Cardiac hypertrophy induces the fetal isoform of genes (rejuvenation), including contractile proteins, ion channels, and natriuretic peptides. Cardiac sympathetic nerve function is known to be altered in cardiac hypertrophy and congestive heart failure. We recently reported that alteration of cardiac sympathetic nerves (CSN) was caused...
Article
Although BTB/POZ family proteins play a critical role in the development of various organs, and are recently known as a substrate adaptor of CUL3 ubiquitin ligases, the involvement of these proteins in heart development remains unknown. We recently isolated the novel protein, RhoBTB3, an 83-kD protein which comprises an N-terminal Rho GTPase resemb...
Article
Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. Lethally irradiated wild-type mi...
Article
Full-text available
Peroxisome proliferator-activated receptor γ coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1α is a short lived and aggregation-prone protein. PGC-1α localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1α formed...
Article
Sympathetic innervation is critical for effective cardiac function. However, the developmental and regulatory mechanisms determining the density and patterning of cardiac sympathetic innervation remain unclear, as does the role of this innervation in arrhythmogenesis. Here we show that a neural chemorepellent, Sema3a, establishes cardiac sympatheti...
Article
Bone marrow mesenchymal stem cells (CMG cells) are multipotent and can be induced by 5-azacytidine to differentiate into cardiomyocytes. We characterized the electrophysiological properties of these cardiomyocytes and investigated their potential for use as transplantable bio-pacemakers. After differentiation, action potentials in spontaneously bea...
Article
Molecular mechanisms regulating the cardiac sensory nervous system remain poorly understood. Cardiac sensory nerve impairment causes silent myocardial ischemia, a main cause of sudden death in diabetes mellitus (DM). The present study focused on the roles of nerve growth factor (NGF) in the regulation of the cardiac sensory nervous system and analy...
Article
Full-text available
Mammalian hearts cannot regenerate. In contrast, zebrafish hearts regenerate even when up to 20% of the ventricle is amputated. The mechanism of zebrafish heart regeneration is not understood. To systematically characterize this process at the molecular level, we generated transcriptional profiles of zebrafish cardiac regeneration by microarray ana...
Data
List of Genes Differentially Expressed During Zebrafish Heart Regeneration Affymetrix probe ID, gene symbol, gene title, functional class, and description are provided for the 662 transcripts that were differentially expressed during zebrafish heart regeneration. The results of our analysis using R include mean signal, mean fc (fold change), and q-...
Data
Expression Patterns of Representative Genes in Each Cluster The differentially expressed genes were grouped into six clusters (I to VI). Each gene cluster is shown separately for illustrative purposes and the representative genes are indicated graphically by plotting dpa versus log 2 (fold change). Cluster I (genes downregulated during heart regene...
Data
Sequence Alignment of Human, Mouse, Xenopus, and Zebrafish PDGF-B The alignments were performed using clustW. The gray boxes indicate homologous regions. The red boxes indicate conserved cysteine residues. Zebrafish PDGF-B shows high homology to other species. (404 KB EPS)
Data
Secreted Factors Tested on Zebrafish Cardiomyocytes for Induction of DNA Synthesis (27 KB DOC)
Data
List of Genes Differentially Expressed during Both Heart and Fin Regeneration (44 KB DOC)
Article
Epimorphic regeneration requires the presence or creation of pluripotent cells capable of reproducing lost organs. Zebrafish fin regeneration is mediated by the creation of blastema cells. Here, we characterize the devoid of blastema (dob) mutant that fails fin regeneration during initial steps, forms abnormal regeneration epithelium, and does not...
Article
Full-text available
Zebrafish fin regeneration requires the formation and maintenance of blastema cells. Blastema cells are not derived from stem cells but behave as such, because they are slow-cycling and are thought to provide rapidly proliferating daughter cells that drive regenerative outgrowth. The molecular basis of blastema formation is not understood. Here, we...
Article
Full-text available
We recently reported that cardiomyocytes could be differentiated from bone marrow mesenchymal stem cells in vitro by 5-azacytidine treatment. In native cardiomyocytes, adrenergic and muscarinic receptors play crucial roles in mediating heart rate, conduction velocity, contractility, and cardiac hypertrophy. We investigated whether these receptors a...
Article
We have isolated a cardiomyogenic cell line (CMG cell) from murine bone marrow stromal cells. Stromal cells were immortalized, treated with 5-azacytidine, and spontaneous beating cells were repeatedly screened for. The cells showed a f ibroblast-like morphology, but the morphology changed after 5-azacytidine treatment in approximately 30% of the ce...
Article
We compared the role of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK)/p90(RSK) cascade in gp130-mediated cardiac hypertrophy with the contribution of the Janus kinase (JAK)/signal transduction and activation of transcription (STAT) and phosphatidyli...
Article
Full-text available
This study was designed to investigate whether angiotensin II induces the interleukin (IL)-6 family of cytokines in cardiac fibroblasts and, if so, whether these cytokines can augment cardiac hypertrophy. Angiotensin II increased IL-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 mRNA by 6.5-, 10.2-, and 2.0-fold, respectively, but did not...
Article
This study was designed to investigate whether insulin-like growth factor-1 (IGF-1) transduces signaling through the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and to assess the upstream signals of serine and tyrosine phosphorylation of STAT family proteins. Primary cultured neonatal rat c...