[Regeneration and formation of physiopathological states by cells derived from the bone marrow].
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Bone Marrow Transplantation↗
Biomedical subjects
Masataka Sata
Publications and source records attributed to Masataka Sata.
Absence of p53 leads to accelerated neointimal hyperplasia after vascular injury.
OBJECTIVE: It has been suggested that deregulated expression of the tumor suppressor protein p53 may play a role in the pathogenesis of occlusive vascular remodeling. However, the role of p53 in cell proliferation and apoptosis in vascular lesions has been controversial. METHODS AND RESULTS: We tested the potential involvement of p53-mediated molecular signaling in lesion formation using a mouse model of vascular injury that may resemble balloon angioplasty. A large wire was inserted into the femoral artery of p53+/+ and p53-/- mice. There was no significant difference in the occurrence of rapid-onset apoptosis, that is, 4 hours after injury. At 2 weeks, the number of proliferating cells in the lesion of p53-/- mice was significantly higher than that observed in p53+/+ mice. The frequency of apoptotic cells was significantly lower in p53-/- mice than in p53+/+ mice. At 4 weeks, the neointimal hyperplasia of p53-/- mice was greater than that of p53+/+ mice. There was no significant difference in the frequency of apoptosis in the lesions. CONCLUSIONS: These results indicate a crucial role of p53 in pathological vascular remodeling after mechanical injury and provide the basis for the development of new therapies targeting p53 for a prophylactic treatment of vascular diseases.
Actins↗
Adrenomedullin augments collateral development in response to acute ischemia.
Expression of adrenomedullin, discovered as a vasodilatory peptide, is markedly up-regulated under pathological conditions such as tissue ischemia and inflammation, which are associated with neovascularization. Here, we tested the hypothesis that overly expressed adrenomedullin may augment collateral flow to ischemic tissues. We induced hindlimb ischemia in wild-type mice and injected a naked plasmid expressing human adrenomedullin or an empty vector into the ischemic muscle, followed by in vivo electroporation. Adrenomedullin markedly enhanced blood flow recovery as determined by Laser Doppler imaging. The mice treated with an empty vector suffered frequent autoamputation of the ischemic toe, which was completely prevented by adrenomedullin. Anti-CD31 immunostaining revealed that adrenomedullin significantly increased capillary density. The angiogenic effect of adrenomedullin was abrogated in endothelial nitric oxide synthase (eNOS)-deficient mice. These results indicate that adrenomedullin may promote collateral growth in response to ischemia through activation of eNOS.
Acute Disease↗
Origin of smooth muscle progenitor cells: different conclusions from different models.
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Animals↗
Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes.
OBJECTIVE: Fas ligand (FasL) is a key cytokine which initiates apoptosis when FasL binds to its receptor, Fas. Cardiac myocytes are generally resistant to Fas-induced apoptosis. However, sublethal dose of doxorubicin (Dox) can sensitize cardiac myocytes to Fas-induced apoptosis. We investigated the molecular mechanism by which Dox sensitizes cardiac myocytes to Fas-induced apoptosis. FLICE inhibitory protein (FLIP) is a key molecule for blocking Fas-induced apoptosis by functioning as a caspase-8 dominant negative. METHODS AND RESULTS: FLIP was constitutively expressed in cultured neonatal rat cardiac myocytes. FLIP protein levels were markedly down-regulated by Dox in a time-dependent and dose-dependent manner. Next, we examined the relation of reactive oxygen species (ROS) by Dox to the expression of FLIP. Both of N-acetylcysteine (NAC) and the combination of superoxide dismutase and catalase restored the decreased FLIP in Dox-treated cardiac myocytes to the basal level. NAC also restored the increased formation of thiobarbituric acid-reactive substance after Dox-treatment. Concurrently, the susceptibility to Fas-mediated apoptosis disappeared with the treatments of the antioxidant agents. Hydrogen peroxide down-regulated FLIP in a dose-dependent fashion and also sensitized cardiac myocytes to Fas-induced apoptosis. CONCLUSIONS: FLIP, an inhibitor of apoptosis induced by cytokines of TNF family, contributes at least partly to Dox-induced sensitization to Fas-mediated apoptosis in cardiac myocytes. The expression of FLIP in cardiac myocytes is regulated by ROS.
Acetylcysteine↗
Little evidence for cell fusion between recipient and donor-derived cells.
Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of the transplant-associated atherosclerosis remains largely unknown. Here, we investigated the origin of the vascular cells that contribute to graft vasculopathy. We performed heterotopic heart transplantation using genetically modified mice that express LacZ or green fluorescent protein (GFP) ubiquitously and constitutively. At 4 weeks after transplantation, the graft coronary arteries developed neointimal hyperplasia, expressing several smooth muscle cell markers. Most of the neointimal cells were composed of recipient cells but not graft medial smooth muscle cells. We seldom detected neointimal cells that were positive for both LacZ and GFP. When we transplanted wild-type cardiac allografts into the chimeric mice whose bone marrow cells had been replaced with those of LacZ-mice or GFP-mice, we observed that most of the neointimal cells were derived from the bone marrow. These findings suggest that recipient bone marrow-derived cells contribute to the pathogenesis of graft arteriosclerosis. Spontaneous cell fusion between recipient and donor-derived cells seems to be a rare event, if it occurs at all.
Animals↗
Sera from liver failure patients and a demethylating agent stimulate transdifferentiation of murine bone marrow cells into hepatocytes in coculture with nonparenchymal liver cells.
BACKGROUND/AIMS: The plasticity of bone marrow cells (BMCs) is shown by their ability to differentiate into mesenchymal as well as endodermal and ectodermal lineages. Transdifferentiation of BMCs into hepatocytes has also been demonstrated, both in vitro and in vivo. In the present study we investigated the effects of liver nonparenchymal cells (NPCs) and sera from liver failure patients (HSLF) on the in vitro transdifferentiation of murine BMCs into hepatocytes. METHODS: Liver NPCs from wild-type mice, and 5-azacytidine-treated BMCs from green fluorescence protein transgenic mice, were cocultured in medium containing HSLF in combination with several cytokines. Hepatocyte-specific gene expression in BMCs was identified by immunocytochemistry and reverse transcription-polymerase chain reaction. RESULTS: Bone marrow cell-derived hepatocyte-like colonies appeared after several days of coculture in medium containing HSLF, oncostatin M (OSM) and hepatocyte growth factor (HGF). These colonies expressed hepatocyte-specific genes. Transdifferentiation was enhanced by 5-azacytidine treatment, and by HSLF, OSM and HGF. It did not take place when the BMCs were separated from the NPCs in a dual chamber dish, or cultured with other mesenchymal cells. CONCLUSIONS: Direct interaction of murine BMCs with liver NPCs, as well as soluble factors in the HSLF and a demethylating agent, strongly stimulate transdifferentiation into hepatocytes.
Animals↗
Circulating vascular progenitor cells contribute to vascular repair, remodeling, and lesion formation.
Exuberant accumulation of smooth muscle cells (SMCs) plays a principal role in the pathogenesis of vascular diseases. It has been assumed that SMCs derived from the adjacent medial layer migrate, proliferate, and synthesize extracellular matrix. Although much effort has been devoted to understanding the molecular pathways regulating migration and proliferation of medial SMCs, no effective therapy to prevent occlusive vascular remodeling has been established. It was recently reported that bone marrow cells substantially contribute to the pathogenesis of vascular diseases, in models of postangioplasty restenosis, graft vasculopathy, and hyperlipidemia-induced atherosclerosis. It was suggested that bone marrow cells may have the potential to give rise to vascular progenitor cells that home in on the damaged vessels and differentiate them into smooth muscle cells or endothelial cells, thereby contributing to vascular repair, remodeling, and lesion formation. The present findings may provide the basis for the development of new therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation, and proliferation of circulating vascular progenitor cells.
Animals↗
Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.
Hematopoietic stem cells (HSCs) are thought to arise in the aorta-gonad-mesonephros (AGM) region of embryo proper, although HSC activity can be detected in yolk sac (YS) and paraaortic splanchnopleura (P-Sp) when transplanted in newborn mice. We examined the role of Notch signaling in embryonic hematopoiesis. The activity of colony-forming cells in the YS from Notch1(-/-) embryos was comparable to that of wild-type embryos. However, in vitro and in vivo definitive hematopoietic activities from YS and P-Sp were severely impaired in Notch1(-/-) embryos. The population representing hemogenic endothelial cells, however, did not decrease. In contrast, Notch2(-/-) embryos showed no hematopoietic deficiency. These data indicate that Notch1, but not Notch2, is essential for generating hematopoietic stem cells from endothelial cells.
Animals↗
Molecular strategies to treat vascular diseases: circulating vascular progenitor cell as a potential target for prophylactic treatment of atherosclerosis.
Atherosclerosis is responsible for more than half of all deaths in Western countries. Numerous studies have reported that accumulation of smooth muscle cells (SMCs) plays a principal role in atherogenesis, post-angioplasty restenosis and transplantation-associated vasculopathy. Although much effort has been devoted to targeting the migration and proliferation of medial SMCs, effective therapy to prevent occlusive vascular remodeling has not been established. Recently, it was suggested that bone marrow-derived precursors can give rise to vascular cells that contribute to the repair, remodeling, and lesion formation of the arterial wall under certain circumstances. This review highlights the recent findings on circulating vascular precursors and describes the potential therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of circulating progenitor cells.
Animals↗
Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice.
Adrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.
Acetylcholine↗
[Myocyte renewal].
In contrast to conventional assumption that myocytes are never renewed after birth, a growing body of evidence suggests that human cardiac myocytes might divide in myocardial infarction and severe heart failure. Bone marrow cells may also contribute to myocyte regeneration, when injected or mobilized into systemic circulation by cytokines. A clinical study demonstrated that intracoronary administration of autologous bone marrow significantly improved the cardiac function after acute myocardial infarction. No adverse effect was found. Cell therapy using adult stem cells is anticipated to be an effective treatment of heart failure.
Bone Marrow Transplantation↗
Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo.
Fas is a widely expressed cell surface receptor that can initiate apoptosis when activated by its ligand (FasL). Whereas Fas abundance on cardiac myocytes increases in response to multiple pathological stimuli, direct evidence supporting its role in the pathogenesis of heart disease is lacking. Moreover, controversy exists even as to whether Fas activation induces apoptosis in cardiac myocytes. In this study, we show that adenoviral overexpression of FasL, but not beta-galactosidase, results in marked apoptosis both in cultures of primary neonatal cardiac myocytes and in the myocardium of intact adult rats. Myocyte killing by FasL is a specific event, because it does not occur in lpr (lymphoproliferative) mice that lack functional Fas. To assess the contribution of the Fas pathway to myocardial infarction (MI) in vivo, lpr mice were subjected to 30 min of ischemia followed by 24 h of reperfusion. Compared with wild-type mice, lpr mice exhibited infarcts that were 62.3% smaller with 63.8% less myocyte apoptosis. These data provide direct evidence that activation of Fas can induce apoptosis in cardiac myocytes and that Fas is a critical mediator of MI due to ischemia-reperfusion in vivo.
Animals↗
G-CSF stimulates angiogenesis and promotes tumor growth: potential contribution of bone marrow-derived endothelial progenitor cells.
Solid tumors require neovascularization for their growth. Recent evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs) contribute to tumor angiogenesis. We show here that granulocyte colony-stimulating factor (G-CSF) markedly promotes growth of the colon cancer inoculated into the subcutaneous space of mice, whereas G-CSF had no effect on cancer cell proliferation in vitro. The accelerated tumor growth was associated with enhancement of neovascularization in the tumor. We found that bone marrow-derived cells participated in new blood vessel formation in tumor. Our findings suggest that G-CSF may have potential to promote tumor growth, at least in part, by stimulating angiogenesis in which bone marrow-derived EPCs play a role.
Animals↗
Iron overload augments angiotensin II-induced cardiac fibrosis and promotes neointima formation.
BACKGROUND: Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. METHODS AND RESULTS: Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. CONCLUSIONS: Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II. In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.
Angiotensin II↗
Gene expression profile during acute rejection in rat-to-mouse concordant cardiac xenograft by means of DNA microarray.
Using a rat-to-mouse concordant cardiac transplantation model and DNA microarrays, we studied the gene expression profiles during acute rejection. We used inbred BALB/c and C3H/He mice and Lewis rats for our study, in which heterotopic cardiac transplantations were performed. Total RNA was isolated from xenografts (Lewis to C3H), allografts (BALB/c to C3H), rat isografts (Lewis to Lewis) and mouse isografts (C3H to C3H) on day 5 following transplantation. We screened for gene expression profiles in the xenografts, allografts, and mouse isografts by means of DNA microarrays. With a murine array, we determined that many IFN-gamma inducible genes were profoundly expressed in both the allografts and xenografts relative to the isografts. Mac-1 was specifically induced in the xenografts relative to the allografts. Using a rat array, we observed that the cardionatrin and atrial natriuretic factors were most profoundly expressed in the xenografts in comparison with the rat isografts. In addition to known genes, many expressed sequence tags were induced in the xenografts. We identified a group of genes, including Mac-1 induced specifically in xenografts, as well as many new genes upregulated in xenografts.
Acute Disease↗
Biphasic effects of statins on angiogenesis.
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Animals↗
Phosphatidylinositol 3-kinase: a key regulator of vascular tone?
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Animals↗