Human mesenchymal stromal cells improve scar thickness without enhancing cardiac function in a chronic ischaemic heart failure model

Few data address the role of human mesenchymal stromal cells (MSCs) in the management of chronic ischaemic heart failure. We assessed their effect in immune-deficient animals. MSCs were cultured from bone marrow of human volunteers. Non-obese diabetes severe combined immunodeficiency (NOD/SCID) gamma null mice were randomly assigned to intramyocardial injection of human MSCs or phosphate-buffered saline 4 weeks after induction of acute myocardial infarction (MI). Echocardiography was performed 4 weeks after MI and 1 and 4 weeks after injection. Donor cell chimerism was assessed by DNA for human Alu sequences 2 and 4 weeks after injection. Histological assessment and quantification of neovascularization were determined 4 weeks after treatment. Donor MSCs at frequencies of 0.006 and 0.001% were present 2 and 4 weeks after cell injection, respectively. The infarcted ventricular wall was significantly thicker in the cohort receiving MSCs compared with control mice. There was no difference in fractional shortening, left ventricular dimensions or scar area between the groups. Small vessel density was also similar between the groups. Human MSCs increased the thickness of the infarcted ventricular wall without improving cardiac function in this chronic ischaemic heart failure model. Further studies are required to assess the benefit of MSCs in this setting.Fil: Dayan, Victor. University Health Network; CanadáFil: Yannarelli, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University Health Network; CanadáFil: Filomeno, Paola. University Health Network; CanadáFil: Keating, Armand. University of Toronto; Canadá. University Health Network; Canad

Development and characterization of a new inbred transgenic rat strain expressing DsRed monomeric fluorescent protein

The inbred rat is a suitable model for studying human disease and because of its larger size is more amenable to complex surgical manipulation than the mouse. While the rodent fulfills many of the criteria for transplantation research, an important requirement is the ability to mark and track donors cells and assess organ viability. However, tracking ability is limited by the availability of transgenic (Tg) rats that express suitable luminescent or fluorescent proteins. Red fluorescent protein cloned from Discosoma coral (DsRed) has several advantages over other fluorescent proteins, including in vivo detection in the whole animal and ex vivo visualization in organs as there is no interference with autofluorescence. We generated and characterized a novel inbred Tg Lewis rat strain expressing DsRed monomeric (DsRed mono) fluorescent protein under the control of a ubiquitously expressed ROSA26 promoter. DsRed mono Tg rats ubiquitously expressed the marker gene as detected by RT-PCR but the protein was expressed at varying levels in different organs. Conventional skin grafting experiments showed acceptance of DsRed monomeric Tg rat skin on wild-type rats for more than 30 days. Cardiac transplantation of DsRed monomeric Tg rat hearts into wild-type recipients further showed graft acceptance and long-term organ viability (>6 months). The DsRed monomeric Tg rat provides marked cells and/or organs that can be followed for long periods without immune rejection and therefore is a suitable model to investigate cell tracking and organ transplantationFil: Montanari, Sonia. University Health Network. Toronto; Canadá. University of Toronto; Canadá. Princess Margaret Cancer Centre. Toronto; CanadáFil: Wang, Xing-Hua. University Health Network. Toronto; CanadáFil: Yannarelli, Gustavo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University Health Network. Toronto; CanadáFil: Dayan, Victor. University Health Network. Toronto; CanadáFil: Berger, Thorsten. University Health Network. Toronto; CanadáFil: Zocche, Larissa. University Health Network. Toronto; CanadáFil: Kobayashi, Eiji. Jichi Medical School. Tochigi; JapónFil: Viswanathan, Sowmya. University Health Network. Toronto; CanadáFil: Keating, Armand. University of Toronto; Canadá. University Health Network. Toronto; Canad

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Human umbilical cord perivascular cells exhibit enhanced cardiomyocyte reprogramming and cardiac function after experimental acute myocardial infarction

We were interested in evaluating the ability of the mesenchymal stromal cell (MSC) population, human umbilical cord perivascular cells (HUCPVCs), to undergo cardiomyocyte reprogramming in an established co-culture system with rat embryonic cardiomyocytes. Results were compared with human bone marrow-derived (BM) MSCs. The transcription factors GATA4 and Mef2c were expressed in HUCPVCs but not BM-MSCs at baseline, and at 7 days increased 7.6 and 3.5-fold respectively, compared with BM-MSCs. Although cardiac-specific gene expression increased in both cell types in co-culture, up-regulation was more significant in HUCPVCs, consistent with Mef2c-GATA4 synergism. Using a lentivector with eGFP transcribed from the a-myosin heavy chain ( a-MHC) promoter, we found that cardiac gene expression was greater in HUCPVCs than BM-MSCs after 14d co-culture (52±17% vs 29±6%, respectively). A higher frequency of HUCPVCs expressed a-MHC protein compared with BM-MSCs (11.6±0.9% vs 5.3±0.3%) however, both cell types retained MSC-associated determinants. We also assessed the ability of the MSC types to mediate cardiac regeneration in a NOD/SCID(gnull) mouse model of acute myocardial infarction (AMI). Fourteen days after AMI, cardiac function was significantly better in celltreated mice compared with control animals and HUCPVCs exhibited greater improvement. Although human cells persisted in the infarct area, the frequency of a-MHC expression was low. Our results indicate that HUCPVCs exhibit a greater degree of cardiomyocyte reprogramming but that differentiation for both cell types is partial. We conclude that HUCPVCs may be preferable to BM-MSCs in the cell therapy of AMI.Fil: Yannarelli, Gustavo Gabriel. University Health Network. Prince Margaret Hospital. Cell Therapy Program; CanadáFil: Dayan, Victor. University Health Network. Prince Margaret Hospital. Cell Therapy Program; CanadáFil: Pacienza, Natalia Alejandra. University Health Network; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lee, Chyan Jang. University Health Network; CanadáFil: Medin, Jeffrey. University Health Network; CanadáFil: Keating, Armand. University Health Network. Prince Margaret Hospital. Cell Therapy Program; Canadá. University of Toronto; Canad

Mesenchymal stromal cells improve cardiac function and left ventricular remodeling in a heart transplantation model

Background: Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in heart transplantation. Bone marrow–mesenchymal stromal cell (BM-MSC) treatment is a potentially effective cell therapy for cardiac disease. We investigated the effects of intravenous delivery of BM-MSCs in the acute phase post-transplant in a heterotopic heart transplantation (HHT) model associated with I/R injury. Methods: Hearts of wild-type Lewis (WT LEW) rats were harvested and transplanted heterotopically into the necks of recipient WT LEW rats. Forty-eight hours after HHT, BM-MSCs were injected intravenously into animals in the experimental group, whereas controls received normal saline (NS). Results: Eight days after BM-MSC injection, fractional shortening of transplanted hearts was significantly higher and left ventricular systolic diameter was lower in the BM-MSC group compared with controls, whereas no differences were found 28 days after infusion. A reduction in ventricular remodeling and cardiac fibrosis was observed by histochemical analysis and confirmed by cardiac magnetic resonance imaging in the BM-MSC group. The perivascular stromal cells’ density and the number of capillaries were increased whereas the number of apoptotic cells decreased significantly in transplanted hearts in the BM-MSC group compared with the NS group. Conclusions: We showed early improvement in cardiac function and subsequent enhanced ventricular remodeling, reduced cardiac fibrosis, augmented neo-vascularization and decreased cardiomyocyte apoptosis of the transplanted heart in a heterotopic transplantation model after intravenous infusion of BM-derived MSCs. Our data suggest that clinical studies with BM-MSCs are warranted to understand their effects on cardiac graft and transplant recipient survival.Fil: Montanari, Sonia. University Health Network; Canadá. University of Toronto; CanadáFil: Dayan, Victor. University Health Network; CanadáFil: Yannarelli, Gustavo Gabriel. University Health Network; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Billia, Filio. Toronto General Hospital; CanadáFil: Viswanathan, Sowmya. University Health Network; CanadáFil: Connelly, Kim A.. Keenan Research Centre; CanadáFil: Keating, Armand. University Health Network; Canadá. University of Toronto; Canad