Pathology of experimental pulmonary bone marrow embolism. II. Post-embolic pulmonary arteriosclerosis and pulmonary hypertension in rabbits receiving an intravenous infusion of allogeneic bone marrow

The author investigated the morphogenesis of pulmonary arteriosclerosis in rabbits at 2 days to 3 months after the infusion of sliced fresh allogeneic bone marrow (500 mg) into the marginal ear vein of 87 rabbits. After 2 to 7 days, granulation tissue was formed in the embolized bone marrow, and new endothelial cells appeared on the surface resulting in recanalization. By 2 weeks, embolized bone marrow developed into fibrous and fibro-fatty plaques in the arterial wall. Moreover, from 4 weeks on, smooth muscle cells and elastic fibers proliferated in the emboli just beneath the new endothelial lining. The intima of non-embolized small arteries showed circumferential fibroelastosis, as the result of arteritis and followed by proliferation of medial smooth muscle cells, with narrowing of vascular lumen. The medial smooth muscle cells play an important role in the morphogenesis of pulmonary arteriosclerosis in bone marrow embolism. Pulmonary arterial pressure gradually increased 1 month as well as 3 months after the infusion. It is considered that narrowing of the vascular lumen resulted from post-embolic pulmonary arteriosclerosis may produce persistent pulmonary hypertension.     

Pathology of experimental pulmonary bone marrow embolism. I. Initial lesions of the rabbit lung after intravenous infusion of allogeneic bone marrow with special reference to its pathogenesis

In order to investigate the initial lesions of pulmonary bone marrow embolism and its pathogenesis, the author studied the pulmonary changes of 70 rabbits during a 24-hour period after the infusion of 500 mg of fresh allogeneic bone marrow into the marginal ear veins. After 30 minutes, leukostasis was observed in the non-embolized small arteries. After 2 hours, leukostasis increased and by 5 to 10 hours, it reached a maximum, still decreased considerably after 24 hours. In the perivascular connective tissue, edema and inflammatory cell infiltration had occurred as a result of increased vascular permeability due to leukostasis. Fifteen minutes after intravenous administration of a single shot of indomethacin (5 mg/kg), the infusion of allogeneic bone marrow was performed. Five hours after the infusion, the suppression of pulmonary vascular leukostasis and interstitial edema were observed. The effect of drugs on morphological changes, however, is extremely small in the group pre-treated with diphenhydramine hydrochloride (3 mg/kg). The author concluded that the mechanical injury of vascular endothelial cells by emboli and the accumulation of leukocytes in the pulmonary vessels may play an important role in the pathogenesis of the initial change of pulmonary bone marrow embolism. It is also suggested that the embolized bone marrow in the small arteries and vasculitis may lead to arteriosclerosis in the future.     

PATHOLOGY OF EXPERIMENTAL PULMONARY BONE MARROW EMBOLISM

In order to investigate the initial lesions of pulmonary bone marrow embolism and its pathogenesis, the author studied the pulmonary changes of 70 rabbits during a 24-hour period after the Infusion of 500 mg of fresh allogeneic bone marrow into the marginal ear veins. After 30 minutes, leukostasis was observed in the non-embolized small arteries. After 2 hours, leukostasis increased and by 5 to 10 hours, it reached a maximum, still decreased considerably after 24 hours. In the perivascular connective tissue, edema and inflammatory cell infiltration had occurred as a result of Increased vascular permeability due to leukostasis. Fifteen minutes after intravenous administration of a single shot of indomethacln (5 mg/kg), the Infusion of allogeneic bone marrow was performed. Five hours after the infusion, the suppression of pulmonary vascular leukostasis and interstitial edema were observed. The effect of drugs on morphological changes, however, is extremely small in the group pre-treated with diphenhydramine hydrochloride (3 mg/kg). The author concluded that the mechanical Injury of vascular endothelial cells by emboli and the accumulation of leukocytes in the pulmonary vessels may play an important role in the pathogenesis of the initial change of pulmonary bone marrow embolism. It is also suggested that the embolized bone marrow in the small arteries and vasculitis may lead to arteriosclerosis in the future.     

Development and regression of pulmonary arterial lesions after experimental air embolism

Summary Repeated systemic venous air embolism produces pulmonary vascular lesions, the nature of which is still a subject of controversy. We investigated the pulmonary arterial lesions produced by repeated air embolism in rabbits, both at light and electron microscopic level. We found that they form a remarkable histopathological entity, consisting of initial pronounced vasoconstriction, combined with severe intimal inflammatory changes. Within 4 days after the last injection of air, peculiar sheet-like structures consisting of oedematous tissue and lined by endothelium, projected into the lumen. These structures probably resulted from the shearing stress of the blood, streaming over the severely oedematous intima. They subsequently became thinner and disappeared after two weeks. Various types of blood-borne and mesenchymal cells were present in the thickened intima and within the sheets. The origin of the latter cells remained undecided. They may originate from medial smooth muscle cells penetrating the internal elastic lamina as well as by transition from blood-borne cells into mesenchymal cells, or both.     

Rat pulmonary artery wall injury by chronic intermittent infusions of Escherichia coli endotoxin. Obliterative vasculitis and vascular occlusion

To examine the effect of intermittent endotoxemia on rat pulmonary artery structure and hemodynamic function we infused purified Escherichia coli endotoxin on four occasions over 3 weeks (at 7-day intervals), through an indwelling catheter placed in the external jugular vein. The fourth infusion of endotoxin was associated with widespread but focal alveolar consolidation, reduced perfusion of small pulmonary arteries by lumen occlusion and obliteration, pulmonary vascular wall injury, and a peripheral leukocytosis (mean +/- SEM total leukocytes, endotoxin 133.5 +/- 23 X 10 mm3, control 12.2 +/- 1.2 X 10 mm3, p less than 0.001) in which polymorphonuclear (PMN) leukocytes predominated at the expense of lymphocytes (p2x less than 0.01). The alveolar wall was thickened and the alveolar space was consolidated by degenerating polymorphonuclear leukocytes, mononuclear cells, lipid laden alveolar macrophages, erythrocytes, fibrin, and cell debris. In regions of alveolar consolidation vessel lumens were either narrowed by subendothelial cell collections that consisted either of mononuclear cells or degenerating mural and inflammatory cells, or they were occluded by degenerating inflammatory cells and cell debris. The walls of occluded vessels were evident only by their residual elastic laminae: remnants of lysed endothelial cells lined the intima and the media consisted of degenerating mural and inflammatory cells. Capillary endothelial cells showed extensive hydropic degeneration and lysis of cell contents. Intimal precursor smooth muscle cells were hypertrophied but were not associated with the appearance of mature smooth muscle cells in the walls of small pulmonary arteries. In regions of less severe alveolar consolidation by inflammatory cells, vessel wall injury was still evident but less marked; precursor smooth muscle cells were hypertrophied; subepithelial and subendothelial collections of fluid and fibrin were present; and plasma membranes of endothelial cells were disrupted. Despite extensive pulmonary vascular injury, chronic intermittent endotoxemia did not produce the structural changes associated with pulmonary hypertension (medial thickening and appearance of medial muscle in previously nonmuscular arteries) nor a significant change in pulmonary artery pressure.     

Circulating progenitors contribute to angiogenesis, vascular repair, and lesion formation

Atherosclerosis is responsible for more than half of all deaths in western countries. Numerous studies have reported that exuberant accumulation of smooth muscle cells plays a principal role in the pathogenesis of vascular diseases. It has been assumed that smooth muscle cells derived from the adjacent medial layer migrate, proliferate and synthesize extracellular matrix. Although much effort has been devoted, targeting migration and proliferation of medial smooth muscle cells, no effective therapy to prevent occlusive vascular remodeling has been established. Recently, we reported that bone marrow cells substantially contribute to the pathogenesis of vascular diseases, in models of post-angioplasty 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 the damaged vessels and differentiate into smooth muscle cells or endothelial cells, thereby contributing to vascular repair, remodeling, and lesion formation. This article overviews recent findings on circulating vascular precursors and describes potential therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of circulating progenitor cells.     

Restitution of aortic wall after sustained necrotizing transmural ligation injury. Role of blood cells and artery cells.

Partial ligation of the rabbit abdominal aorta with fine silk suture for 48 hours produced a circular band of transmural necrosis. On release of the ligature, blood cells from the lumen and from adventitial vasa vasorum, as well as cells derived by mitosis from the adjacent surviving endothelium and media, participated in the restitution of a continuous endothelial lining and an intact media containing well-differentiated smooth muscle cells within normal medial lamellar units. Initial deposition of a layer of blood platelets on the fibrillar material coating the denuded lumenal surface was followed by ingress from the lumen of polymorphonuclear granulocytes and mononuclear cells. These changes preceded the appearance of mitoses in surviving endothelial and medial smooth muscle cells at the margin of injury. By 24 hours, poorly differentiated cells had accumulated in the central portion of the intima and inner media. Similar cells formed a more extensive, nearly complete lumenal layer which was eventually continuous with and indistinguishable from the adjacent uninjured endothelium. By 7 days, smooth muscle cells repopulated the media, and a collection of less differentiated cells persisted between the restored endothelium and media. By 28 days, the only deviation from normal arterial structure was the persistence at the point of ligature of intimal thickening, consisting of smooth muscle cells and collagen and elastin fibers. Though still present at 6 weeks, this zone became increasingly compact and layered. There was no evidence that fibrin thrombus formation was a consistent feature of the initial reaction or that it played a role in the healing process or in the formation of the intimal lesion. Despite complete circumferential necrosis at the site of ligature, there was no evidence of medial rupture or intramural hemorrhage.     

ULTRASTRUCTURAL STUDIES ON HUMAN ARTERIOSCLEROSIS-COMPARISON BETWEEN HYPERTENSIVE AND NORMOTENSIVE GROUPS

Systematic observation of arteriosclerosis by electron microscope was made on small arteries and arterioles of the stomach which were respected from 5 hypertensive cases and 6 normotensive cases who underwent surgery for gastric carcinoma or ulcer and which were fixed by perfusion with glutaraldehyde. Concurrently, three rabbits were used for animal experiments. Upon placing electrodes in the gastric wall of the rabbits, electric stimulation with 2.0 volt D.C. was repeated intermittently during the period of 5 to 12 days.
Repeated contraction of vessels resulted in crush-up effect of smooth muscle cells beneath the internal elastic lamina and in transition of irregularly minced cytoplasms into small osmophilic particles. At the same time dark cells appeared among the smooth muscle cells in the vicinity. The same findings were frequently noted in the lesions of gastric artery of man particularly in the hypertensive group. It was apparent that repeated angiospasm is an important factor for the histogenesis of sclerotic vascular lesion.
The cells proliferating beneath the endothelial cells in arteriosclerosis were smooth muscle cells, and the direction of the proliferated smooth muscle cell layers did not necessarily conform with that of the media. They originated in the media and penetrated through the fenestrae of the internal elastic lamina.
Fibrinoid necrosis and hyalinous thickening of arterioles were observed fairly frequently in the hypertensive group but always accompanied with intensive irregular atrophy or disappearance of the medial smooth muscle cells.
Vascular lesions with initial thickening showed formation of new elastic lamina most of which was elastic fibers consisting of microfibrillar components. The additional formation of elastic fibers was particularly strong in the hypertensive group as the whole.     

Vascular remodeling in pulmonary hypertension

Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase, and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting.     

Temporal and spatial characterization of cellular constituents during neointimal hyperplasia after vascular injury: Potential contribution of bone-marrow-derived progenitors to arterial remodeling

BACKGROUND: Exuberant smooth muscle cells (SMCs) hyperplasia is the major cause of postangioplasty restenosis. We suggested that circulating smooth muscle progenitor cells might contribute to lesion formation after vascular injury. METHODS: We extensively investigated the cellular constituents during neointimal formation after mechanical vascular injury. RESULTS: A large wire was inserted into the mouse femoral artery, causing complete endothelial denudation and marked enlargement of the lumen with massive apoptosis of medial SMCs. At 2 h, the injured artery remained dilated with a thin media containing very few cells. A scanning electron microscopy showed fibrin and platelet deposition at the luminal side. One week after the injury, CD45-positive hematopoietic cells accumulated at the luminal side. Those CD45-positive cells gradually disappeared, whereas neointimal hyperplasia was formed with alpha-smooth muscle actin (SMA) positive cells. Bone marrow cells and peripheral mononuclear cells differentiated into alpha-SMA-positive cells in the presence of PDGF and basic FGF. Moreover, in bone marrow chimeric mice, bone-marrow-derived cells substantially contributed to neointimal hyperplasia after wire injury. CONCLUSION: These results suggest that early accumulation of hematopoietic cells may play a role in the pathogenesis of SMC hyperplasia under certain circumstances.     

移植骨髓间充质干细胞预防野百合碱诱导的肺动脉高压

背景：干细胞移植治疗肺动脉高压有一定疗效。 目的：观察骨髓间充质干细胞移植治疗肺动脉高压的效果及并探讨其作用机制。 方法：采用密度梯度离心法体外培养、纯化、扩增获得大鼠骨髓间充质干细胞,经荧光染料标记后备用。大鼠皮下注射野百合碱建立肺动脉高压模型,建模后1周将大鼠随机分为3组,干细胞移植组和肺动脉高压组大鼠皮下注射野百合碱建立肺动脉高压模型,1周后干细胞组大鼠经舌下静脉注射骨髓间充质干细胞悬液,肺动脉高压组注射等量不含干细胞的培养液,对照组皮下注射等量生理盐水。 结果与结论：移植后2周,与野百合碱诱导的肺动脉高压大鼠相比干细胞移植组血流动力学参数及右心室与体质量之比明显改善(P < 0.05);肺血管重构程度减轻(P < 0.05)。荧光显微镜下发现干细胞组移植的骨髓间充质干细胞在大鼠体内能存活至少2周,部分干细胞能转化为血管平滑肌细胞。说明静脉移植骨髓间充质干细胞能明显改善野百合碱造成的肺动脉高压大鼠肺血管和右心室结构的损伤。     

Administration of chronic intravenous platelet-activating factor induces pulmonary arterial atrophy and hypertension in rabbits

Platelet-activating factor (PAF), a lipid mediator of inflammation, was given by continuous intravenous infusion to rabbits for 2, 4, and 8 weeks, and morphologic and hemodynamic findings were correlated. Pulmonary arterial pressure (PAP), cardiac output, and right atrial pressure were measured, and total pulmonary resistance was calculated. In cross-sections of intraparenchymal pulmonary arteries, internal elastic lamina circumference and intimal and medial areas were measured. The ratio of the weight of the right ventricle to the weight of the left ventricle plus septum, and alveolar/artery ratios were also obtained. In bronchoalveolar lavage fluid, total and differential cell counts were determined. After 2 weeks of PAF treatment, PAP rose by 4 mm Hg. The increase in PAP became significant by 4 weeks and remained so at 8 weeks of treatment. Total pulmonary resistance nearly doubled by 2 weeks and continued to be elevated throughout 8 weeks of PAF treatment. Cardiac output fell significantly to 0.26 liters/minute at 2 weeks of PAF treatment and remained low at 4 weeks. By 8 weeks of treatment, it normalized. The significant rise in total pulmonary resistance at 2 and 4 weeks correlated with the rise in PAP and the fall in cardiac output. The alveolar/artery ratio was increased at 2 weeks of treatment and progressively increased at 4 and 8 weeks, reaching statistical significance at 8 weeks. In intra-acinar arteries, after 2 weeks of treatment, there was a reduction in total cross-sectional area (within the external elastic lamina), medial area, and internal elastic lamina circumference measured by computerized image analysis of 5-microns thick Verhoeff Van Gieson-stained sections. Changes in total area, medial area, and internal elastic lamina circumference persisted after 4 and 8 weeks of treatment. In preacinar arteries, similar changes occurred that were significant only after 8 weeks of treatment. Other findings apparent at 2 weeks of treatment included right ventricular hypertrophy and a marked decline in the number of macrophages and lymphocytes recovered from bronchoalveolar lavage fluid. We conclude that chronic intravenous infusion of PAF in rabbits induces remodeling of pulmonary arteries, specifically reduction of the internal elastic lamina, with consequent narrowing of arterial lumens producing increased pulmonary vascular resistance and pulmonary hypertension. We attribute the increase in alveolar/artery without evident vessel obliteration, to a shortening of arterial length, which is of insufficient magnitude to overcome the effect of vessel narrowing on vascular resistance.     

Perfusion bioreactor for small diameter tissue-engineered arteries

A scaleable perfusion bioreactor has been developed for tissue engineering of small diameter arterial constructs. This modular bioreactor allows for dynamic sequential seeding of smooth muscle and endothelial cells, biomechanical stimulation of cells during culture, and monitoring of tissue growth and maturation. Bovine aortic smooth muscle and endothelial cells were seeded onto porous tubular poly(glycolic acid) nonwoven scaffolds and cultured in the bioreactor under pulsatile flow conditions for up to 25 days. Cell proliferation was more than 3-fold after 4 days, smooth muscle cells expressed differentiated phenotype after 16 days, and collagen and elastin were distributed throughout the construct after 25 days of culture. In bioreactor experiments in which the construct lumen was seeded with endothelial cells by perfusion after 13 days of smooth muscle cell culture, endothelial cell seeding efficiency was 100%, and a confluent monolayer was observed in the lumen within 48 h. These data demonstrate that this perfusion bioreactor supports sequential seeding of constructs with smooth muscle and endothelial cells. Dynamic culture under pulsatile flow leads to cellular expression of differentiated function and extracellular matrix deposition toward the development of tissue-engineered arterial constructs.     

内皮-间充质转化在肺动脉高压发病机制中的研究进展

正肺动脉高压(pulmonary hypertension,PH)是由多种已知和未知原因引起的肺循环血压异常升高的一种病理生理综合症,主要累及心血管及呼吸系统~([1-2])。根据2015年最新PH的临床分型,PH分为动脉型肺动脉高压(pulmonary arterial hypertension,PAH)、左心疾病所致PH、肺部疾病或缺氧所致PH、     

Vascular potency of Sus scrofa bone marrow-derived mesenchymal stem cells: a progenitor source of medial but not endothelial cells

Short-term thrombotic occlusion and compliance mismatch hamper clinical use of synthetic small-diameter tissue engineered vascular grafts. It is felt that preconditioning of the graft with intimal (endothelial) and medial (vascular smooth muscle) cells contributes to patency of the graft. Autologous, non-vessel-derived cells are preferred because of systemic vascular pathology and immunologic concerns. We tested in a porcine model whether cultured bone marrow-derived mononuclear cells, also referred to as mesenchymal stem cells (MSC), are a potential source of intimal or medial cells in vascular tissue engineering. We show that MSC cultured in endothelial medium do not gain an endothelial phenotype or functional characteristics, even after enrichment for CD31, culturing under flow, treatment with additional growth factors (vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)-2), or co-culture with microvascular endothelial cells (EC). On the other hand, we show that MSC cultured in MSC medium, but not in smooth muscle cell medium, show phenotypical and functional characteristics of vascular smooth muscle cells. We conclude that bone marrow-derived MSCs can be used as a bona fide source of medial, but not EC in small-diameter vascular tissue engineering.     

大鼠骨髓间充质干细胞体外向血管平滑肌样细胞的诱导分化

背景：有研究表明,血管外膜成纤维细胞被激活早期参与动脉粥样硬化及血管再狭窄的形成,另有研究表明,骨髓间充质干细胞有部分黏附分化参与血管重塑,实验拟从血管外膜成纤维细胞与骨髓间充质干细胞之间相互作用的角度,来探讨动脉硬化及血管损伤后再狭窄过程中的可能机制。 目的：观察骨髓间充质干细胞与血管外膜成纤维细胞直接接触培养后,骨髓间充质干细胞形态改变及表达血管平滑肌肌动蛋白的情况。 方法：将骨髓间充质干细胞(DAPI标记细胞核)与外膜成纤维细胞按一定的比例混合培养7 d,细胞单独培养作对照,显微镜下观察细胞形态变化,免疫荧光检测骨髓间充质干细胞平滑肌肌动蛋白表达的情况。 结果与结论：骨髓间充质干细胞与血管外膜成纤维细胞共培养后,可见骨髓间充质干细胞的细胞核蓝染(DAPI标记细胞核)、胞浆红染(平滑肌肌动蛋白阳性)的双标细胞出现,且随培养时间的延长,骨髓间充质干细胞的平滑肌肌动蛋白表达阳性率明显增高。结果可见与血管外膜成纤维细胞直接接触有诱导骨髓间充质干细胞向血管平滑肌样细胞分化的趋势。     

Tissue-engineered blood vessels with endothelial nitric oxide synthase activity

Nondegradable synthetic polymer vascular grafts used in cardiovascular surgery have shown serious shortcomings, including thrombosis, calcification, infection, and lack of growth potential. Tissue engineering of vascular grafts with autologous stem cells and biodegradable polymeric materials could solve these problems. The present study is aimed to develop a tissue-engineered vascular graft (TEVG) with functional endothelium using autologous bone marrow-derived cells (BMCs) and a hybrid biodegradable polymer scaffold. Hybrid biodegradable polymer scaffolds were fabricated from poly(lactide-co-epsilon-caprolactone) (PLCL) copolymer reinforced with poly(glycolic acid) (PGA) fibers. Canine bone marrow mononuclear cells were induced in vitro to differentiate into vascular smooth muscle cells and endothelial cells. TEVGs (internal diameter: 10 mm, length: 40 mm) were fabricated by seeding vascular cells differentiated from BMCs onto PGA/PLCL scaffolds and implanted into the abdominal aorta of bone marrow donor dogs (n = 7). Eight weeks after implantation of the TEVGs, the vascular grafts remained patent. Histological and immunohistochemical analyses of the vascular grafts retrieved at 8 weeks revealed the regeneration of endothelium and smooth muscle and the presence of collagen. Western blot analysis showed that endothelial nitric oxide synthase (eNOS) was expressed in TEVGs comparable to native abdominal aortas. This study demonstrates that vascular grafts with significant eNOS activity can be tissue-engineered with autologous BMCs and hybrid biodegradable polymer scaffolds.     

Smooth muscle cell proliferation in the occluded rat carotid artery: lack of requirement for luminal platelets.

The relationship of intimal smooth muscle cell proliferation in the permanently occluded rat carotid artery to the presence or absence of luminal platelets was examined. Blood was rinsed from the arterial lumen immediately after occlusion and was replaced by autologous, citrated platelet-rich plasma (PRP, 6 to 20 X 10(5) platelets/microliter) or filtered platelet-poor plasma (PPP, less than 100 platelets/microliter). Occluded arteries were studied after 1 to 28 days by light and electron microscopy. Events occurring within the first 2 days included fibrin clot formation, endothelial degeneration and denudation, transmural migration of polymorphonucelar leukocytes and monocytes, and, in PRP-filled arteries, degranulation and disappearance of platelets. By 7 days a neointima was formed by macrophages and undifferentiated cells. The latter cells had some features of vascular smooth muscle cells and were apparently derived from medial cells which traversed the internal elastic lamina. After 14 days, identifiable smooth muscle cells emerged as the predominant cell type in a rapidly growing intimal plaque. No differences could be discerned between arteries originally filled with PRP or PPP. This experimental model is similar to atherosclerosis in dimensions of avascular area and in coexistence of degenerative, inflammatory, and proliferative processes. Cell proliferation deep within an atherosclerotic plaque could be initiated by factors other than platelets, perhaps by products of inflammatory cells.     

骨髓间质干细胞在扩张型心肌病微环境中的分化研究

目的：探讨骨髓间质干细胞（MSCs）自体移植后在扩张型心肌病（DCM）微环境中分化为心肌细胞和血管内皮细胞的可行性。 方法： 用健康日本大耳白兔分离培养MSCs，盐酸阿霉素耳缘静脉注射复制兔DCM模型，将5溴脱氧尿嘧啶(BrdU)标记的MSCs移植到扩张型心肌病心肌内,4周后观察移植细胞的增殖分化情况。 结果： 细胞移植4周后，可以在实验组心肌内找到BrdU标记的阳性细胞，且一部分表现为心肌特异性肌钙蛋白T（troponin T）染色阳性，一部分Ⅷ因子相关抗原染色阳性并参与形成新生血管，对照组中没有发现。 结论： MSCs自体移植到扩张型心肌病后可以分化为心肌细胞和血管内皮细胞。