Age-dependent availability and functionality of bone marrow stem cells in an experimental model of acute and chronic myocardial infarction

The aim of this study was to investigate the effect of aging and timing of left ventricular ischemic injury on the availability and functionality of stem cells. We studied young and aged male inbred Lewis rats that were used as donors of bone marrow mononuclear cells (BM-MNCs), divided in four experimental groups: controls, sham operated, 48 h post-myocardial infarction (MI), and 28 days post-MI. In vitro studies included flow cytometry analysis, hematopoietic colony-forming capacity, and invasion assays of migration capacity. BM-MNCs from these groups were transplanted in female rats after MI induction. Late engraftment was evaluated by real-time PCR of the SRY chromosome. Percentage of CD34+/CD45+(low) cells was similar among different experimental groups in young rats, but was significantly higher in aged animals (p < 0.001), particularly 28 days post-MI. KDR+/CD34+ cells were increased 48 h after MI and decreased 28 days post-MI in young animals, while they were profoundly reduced in the aged group (p < 0.001). Triple staining for CD44+/CD29+/CD71+ cells was similar in different groups of aged rats, but we observed an intense increase 48 h post-MI in young animals. Colony-forming units and cytokine-induced migration were significantly attenuated 28 days after the MI. Late engraftment in infarcted transplanted female hearts was present, but considerably heterogeneous. Finally, recovery of left ventricular systolic function in transplanted female recipients was significantly influenced by donors' BM-MNCs groups (p < 0.01). We have demonstrated that aging and timing of myocardial injury are factors that may act synergistically in determining stem cell availability and function. Such interaction should be considered when planning new cell therapy strategies for acute and chronic ischemic heart disease in the clinical arena.     

Mast cells activation contribute to small intestinal ischemia reperfusion induced acute lung injury in rats

BackgroundSmall intestinal ischemia-reperfusion (IIR) injury may lead to severe local and remote tissue injury, especially acute lung injury (ALI). Mast cell activation plays an important role in IIR injury. It is unknown whether IIR mediates lung injury via mast cell activation.MethodsAdult SD rats were randomized into sham operated group (S), sole IIR group (IIR) in which rats were subjected to 75 min of superior mesenteric artery occlusion followed by 4 h reperfusion, or IIR being respectively treated with the mast cell stabilizer Cromolyn Sodium (IIR + CS group), with the tryptase antagonist Protamine (IIR + P group), with the histamine receptor antagonist Ketotifen (IIR + K group), or with the mast cell degranulator Compound 48/80 (IIR + CP group). The above agents were, respectively, administrated intravenously 5 min before reperfusion. At the end of experiment, lung tissue was obtained for histologic assessment and assays for protein expressions of tryptase and mast cell protease 7(MCP7). Pulmonary mast cell number and levels of histamine, TNF-α and IL-8 were quantified.ResultsIIR resulted in lung injury evidenced as significant increases in lung histological scores (P < 0.05 IIR vs. S), accompanied with concomitant increases of mast cell counts and elevations in TNF-α and IL-8 concentrations and reductions in histamine levels (all P < 0.05 IIR vs. S). IIR also increased lung tissue tryptase and MCP7 protein expressions (all P < 0.05, IIR vs. S). Cromolyn Sodium, Ketotifen and Protamine significantly reduced whilst Compound 48/80 aggravated IIR mediated ALI and the above biochemical changes (P < 0.05).ConclusionsMast cells activation play a critical role in IIR mediated ALI.     

Bone marrow stem cells contribute to healing of the kidney

A variety of recent studies support the existence of pathways, in adult humans and rodents, that allow adult stem cells to be surprisingly flexible in their differentiation repertoires. Termed plasticity, this property allows adult stem cells, assumed until now to be committed to generating a fixed range of progeny, on relocation to switch to make other specialized sets of cells appropriate to their new niche. Cells normally present within the bone marrow seem particularly flexible and are able to contribute usefully to many recipient organs. In studies of the liver, bone marrow-derived cells are seen with specialized structural and metabolic adaptations commensurate with their new locations, and these may be abundant, even sufficient, to rescue recipient mice from genetic defects and with evidence that they have proliferated in situ. In the kidney, several studies provide evidence for the presence of "reprogrammed" cells, but in most, it remains possible that cells arrive and redifferentiate but are no longer stem cells. Nevertheless, that appropriately differentiated cells are delivered deep within organs simply by injection of bone marrow cells should make us think differently about the way organs regenerate and repair. Migratory pathways for multipotential cells could be exploited to effect repairs using an individual's own stem cells, perhaps after gene therapy. This concept makes it clear that a transplanted organ would in time become affected by the genetic susceptibilities of the recipient, because of phenotypes that are expressed when trafficking cells incorporate and differentiate.     

ICD-10 codes detect only a proportion of all head injury admissions.

Despite criticism, the codes covering traumatic brain injury under the International Classification of Diseases have been widely used for sample collection in the epidemiological studies of head injury. Data have been collected from an Accident and Emergency department's (A&E's) case register on all head injury admissions to hospitals from a defined geographic area between 1 April 1996 and 31 March 1997, and compared with the list collected from the heath authority's central database by using the ICD-10 codes. Thirty seven per cent of the names in the A&E register appeared in the ICD-10 list, and 41% of the names in the ICD-10 list appeared in the list collected from the A&E department. The incidence of reported head injury was found to be three times higher among the 0-15 years age group compared with the 16-64 years age group (3.3% compared with 1% of the population). Among the 16-64 years age group, the peak rates of admission to hospital were in the months of February and August. Approximately 14% of all the head injury admissions stayed in hospital for more than 72 hours, another 14% stayed between 48 and 72 hours, and the rest (72%) stayed for less than 48 hours.     

Fetal mesenchymal stem cells ameliorate acute lung injury in a rat cardiopulmonary bypass model

Background

Systemic inflammation after prolonged cardiopulmonary bypass (CPB) can cause serious multiorgan system dysfunction. Mesenchymal stem cells (MSCs) are reported to reduce inflammation and attenuate immune response. We have focused on fetal membrane (FM) as a source to provide a large number of MSCs (FM-MSCs). Allogeneic administration of FM-MSCs has been reported to mitigate autoimmune myocarditis or glomerulonephritis. The aim of this study was to investigate whether allogeneic FM-MSCs attenuate systemic inflammatory responses and lung injury in a rat CPB model.

Replacement of myocardium with a Dacron prosthesis for complications of acute myocardial infarction

From July 1983 to April 1986, four patients (three with ventricular septal perforations and one with left ventricular free-wall rupture) underwent replacement of the myocardium with a Dacron prosthesis for complications of acute myocardial infarction. There were three males and one female, ages ranging from 53 to 70 years (mean 63.3). Three of the four patients survived; the one with the ventricular septal perforation died of severe cardiac failure five days after operation. Replacement of the infarcted myocardium with a Dacron prosthesis seems to be an excellent operative technique for the treatment of complications of acute myocardial infarction when the left ventricular cavity is predicted to be small after resection of the myocardium.     

Survival of bone marrow-derived mesenchymal stem cells in a xenotransplantation model.

Mesenchymal stem cells (MSCs) are immunoprivileged and the allogeneic MSCs implantation has been used to facilitate tissue repairs such as bone and cartilage defect. The present study aimed to investigate the feasibility of xenogeneic MSCs implantation. Green fluorescent protein (GFP) transgenic rat bone marrow-derived MSCs were loaded into HA/TCP Skelite blocks and implanted intramuscularly into the quadriceps of the MF1 and SCID mice. After 11 weeks, the implants were harvested and processed for further examinations. The peripheral blood mononuclear cells of each animal were also collected to measure the in vitro immune responses using mixed lymphocyte culture and cytotoxic assay. In the MF1 mice, some surviving MSCs were found in the explants after 11 weeks of implantation, but there was no sign of new bone formation as neither osteocalcin mRNA nor osteoid tissues were detected in the explants; the lymphocyte proliferation and cytotoxicity against donor MSCs were significantly increased in the animals with the xenogeneic MSCs implantation compared with the control littermates without transplantation. In the control SCID mice, osteoid tissues derived from the implanted MSCs were found in the explants; no difference of lymphocyte proliferation and cytotoxicity against the donor MSCs was detected between the SCID mice with or without MSCs implantation. The data suggested that rat MSCs survived the 11 weeks of xenotransplantation in the MF1 mice, but the increased host immune sensitization led to the impaired in vivo osteogenesis potential of MSCs.     

Epicardial deposition of endothelial progenitor and mesenchymal stem cells in a coated muscle patch after myocardial infarction in a murine model

OBJECTIVES: To assess, using an in vivo engraftment strategy combining bone marrow cell (BMC) transplantation and tissue cardiomyoplasty, the functional outcome of distinct vascular progenitor cell therapy (endothelial progenitor (EPC) and mesenchymal stem (MSC) cells) at distance of myocardium infarction (MI). The study was also designed to test whether scaffold mixing progenitors with unfractionated BMC could improve progenitor recruitment in the damaged myocardium. METHODS: To track engrafted progenitor cells in vivo, cultured murine MSC and EPC were transduced with eGFP lentiviruses. Thirty days after cryogenical induction of MI, C57BL/6J mice were randomized to receive muscle patch placement coated or not (control group), labeled EPC or MSC mixed to the ration of 1:10, or not with unfractionated BMC. Two weeks after transplantation, cardiac function was recorded and heart sections were examined to detect GFP-labeled progenitor cells and analyze cell differentiation. RESULTS: This study showed that either type of mono cell therapy improved angiogenesis and cell survival in the scar but only MSC exhibited the capacity to invade the scar. We found no evidence of myocardial or vascular regeneration from progenitor cells. Engraftment of the progenitors/unfractionated BMC mix increased repopulation and thickness of the scar. CONCLUSION: Combined therapy with unfractionated BMC and expanded MSC appeared thus promising for scar repopulation.     

Undifferentiated mesenchymal stem cells seeded on a vascular prosthesis contribute to the restoration of a physiologic vascular wall

BACKGROUND: We evaluated the possibility of restoring a physiologic vascular wall using undifferentiated mesenchymal stem cells (MSCs) seeded on a polyurethane vascular prosthesis. METHODS: Undifferentiated MSCs were seeded on a vascular prosthesis and implanted into Wistar male rats (weight, 350 g) to investigate differentiation into smooth muscle cells and to determine graft endothelialization in vivo. RESULTS: Seeded or nonseeded grafts were surgically implanted. Undifferentiated MSCs were first labelled for green fluorescent protein. After 2 weeks in vivo, MSC that were initially self-expanded on the graft in a monolayer were organized in a multicellular layer mimicking media of aortic adjacent wall. They coexpressed green fluorescent protein and smooth muscle proteins that were not present before the in vivo engraftment, indicating that in vivo conditions induced smooth muscle protein maturation. Undifferentiated MSC showed an electrophysiologic profile quite different than mature smooth muscle cells. In both in vitro- and in vivo-differentiated MSCs, adenosine triphosphate, an IP(3)-dependent agonist, induced an increase in calcium similar to that which occurred in mature smooth muscle cells. However, MSCs failed to respond to caffeine, a ryanodine receptor activator, indicating the absence of mature calcium signaling, and finally, contraction was absent. Endothelialization attested by immunohistology and scanning electron microscopy was greater in MSC-seeded grafts that prevent thrombosis. CONCLUSION: Only partial smooth muscle cell differentiation of MSCs resulted when seeded on vascular grafts, but MSCs spontaneously restore a media-like thick wall. Mesenchymal stem cells have a positive impact on in vivo endothelialization in rats that supports their potential for use in vascular surgery. CLINICAL RELEVANCE: Thrombosis of vascular prostheses is a major complication of surgery. We showed on rat aorta that mesenchymal stem cells seeded on polyurethane patch restore endothelium. It also induced incomplete smooth muscle differentiation. In the future, stem cell could prevent thrombosis of vascular prostheses.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.     

心肌梗死后移植骨髓间充质干细胞后全身细胞的分布

Objective To study the systemic distribution of bone marrow derived mesenchymal stem cells (MSCs) 24 h and 2 weeks after cell injection into the border zone of myocardial infarction area. Methods MSCs from male SD rats were labeled with Bromodeoxyuridine (BrdU). Three weeks after in-duction of myocardial infarction,female SD rats were randomized into 2 groups. Labeled cells (3 × 10 ,50 μl) were injected into the border zone of infarcted area in the one group (n = 12) ,and PBS of equal vol-ume was injected into the border zone of infarcted area in the other group ( n = 8 ). The systemic distribu-tion of MSCs was evaluated through real-time PCR and immunohistochemistry at time points of 24 h and 2 weeks after injection, respectively. Results Cells injected into border zone of infarcted area were distribu-ted to extra-cardiac organs such as spleen,lung and liver. Twenty-four h after injection,cells mainly con-centrated in the heart (467 467 ± 191 387) ,while obvious cell loss was noted in all organs including the heart ( 112 388 ±43 751 ) 2 weeks after injection. Of immunostaining were consistent with those of real-time PCR. Conclusion After injected into the border zone of infarcted area, MSCs mainly gathered in the heart with distributions into spleen, lung, and liver. However, substantial number of cells lost with pro-longed time span.