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Greater Long-Term Effects of Mesenchymal Stem Cells Over BM-MNC in Chronic Myocardial Infarction

In a groundbreaking study, it was found that the transplantation of mesenchymal stem cells (MSCs) induced significant long-term improvements in cardiac function and tissue metabolism compared to bone marrow mononuclear cells (BM-MNC) in rat models of chronic myocardial infarction. The MSCs not only reduced infarct size and fibrosis but also promoted revascularization, likely through paracrine mechanisms enhancing angiogenesis. These findings highlight the potential of MSC therapy as a regenerative strategy in cardiovascular diseases.

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Greater Long-Term Effects of Mesenchymal Stem Cells Over BM-MNC in Chronic Myocardial Infarction

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  1. Universidad deNavarra CENTRO DE INVESTIGACIÓN MÉDICA APLICADA TRANSPLANTATION OF MESENCHYMAL STEM CELLS EXERTS A GREATER LONG-TERM EFFECT THAN BM-MNC IN CHRONIC MYOCARDIAL INFARCTION IN RAT MANUEL Mª MAZO VEGA

  2. Cardiovascular diseases: • First cause of mortality • Myocardial infarction: 12,6% MATERNAL AND PERINATAL COND, NUTRITIONAL STATE 30% CANCER+RESP DISEAS +DIABETES 22% CARDIOVASCULAR DISEASES 30% INJURIES 9% OTHER CHRONIC DISEAS. 9% MYOCARDIAL INFARCTION The world health report 2004, World Health Organization

  3. PHARMACOLOGICAL SURGICAL MYOCARDIAL INFARCTION: TREATMENTS REGENERATIVE Gene Therapy Cell Therapy Nitrates Aspirin ACEi ARB Aldosterone antagonists Estatins Beta-Blockers Inflammatory cytokines antagonists Neutral endopeptidase inhibitors Reperfusion Transplant

  4. STEM CELL THERAPY

  5. STEM CELL THERAPY

  6. SPRAGUE-DAWLEY RAT (+Cyclosporin) Phenotype Differentiation Histological Analysis Infarct Implant (106 cell) RT1A+ CHONDROCYTE -30 d +0 d +7 d +14 d +30 d +90 d RT1B- CD44+ Eco Eco microPET Eco microPET BM-MNC GFP+ ADIPOCYTE CD31- CD73+ MSC GFP+ CD45- CD90+ OSTEOCYTE EXPERIMENTAL DESIGN GFP+ S-D RAT 5-6 weeks

  7. PRE-IMPLANT 3 MONTHS RESULTS: CARDIAC FUNCTION * 60 * 50 40 % LVEF 30 20 10 0 MEDIUM BM-MNC MSC

  8. PRE-IMPL 3 MONTHS RESULTS: TISSUE METABOLISM A C 85 ** 80 MEDIUM % 18F-FDG UPTAKE (ALL SEGMENTS) 75 70 65 60 MEDIUM BM-MNC MSC B BM-MNC * 60 55 % 18F-FDG UPTAKE (INF. SEGMENTS) 50 45 40 MSC 35 MEDIUM BM-MNC MSC

  9. 1 WEEK 2 WEEKS 1 MONTH 3 MONTHS C A B D MEDIUM G E F H BM-MNC K I J L MSC RESULTS: ENGRAFTMENT

  10. MEDIUM MEDIUM BM-MNC BM-MNC MSC MSC RESULTS: INFLAMMATION C D A B CD68TOPRO3 CD68TOPRO3 CD68TOPRO3 ** 400 300 INFARCT CD68+/mm2 200 100 0 1 WEEK 2 WEEKS 1 MONTH MEDIUM BM-MNC MSC ** G H F E GFP CD68TOPRO3 GFP CD68TOPRO3 GFP CD68TOPRO3 ** 2500 2000 ** PERI-INFARCT CD68+/mm2 1500 ** 1000 ** 500 0 1 WEEK 2 WEEKS 1 MONTH MEDIUM BM-MNC MSC J L M I K TOPRO3 GFP CD68 MERGED MERGED

  11. A B * * * RESULTS: INFLAMMATION

  12. RESULTS: MECHANISMS OF ACTION C D A B CAV1DAPI CAV1DAPI CAV1DAPI * 1200 900 CAPILLARIES/mm2 600 300 0 MEDIUM BM-MNC MSC MEDIUM BM-MNC MSC ** G H F E αSMADAPI αSMA DAPI αSMA DAPI ** 3 ** 2,5 2 % SM-POSITIVE AREA 1,5 1 0,5 0 MEDIUM BM-MNC MSC MEDIUM BM-MNC MSC K L J I 25 20 * 15 % INFARCTED LV 10 5 0 MEDIUM BM-MNC MSC MEDIUM BM-MNC MSC O P N M 75 70 * 65 % CVF 60 55 MEDIUM BM-MNC MSC 50 MEDIUM BM-MNC MSC

  13. 150 150 100 100 50 50 PCNA αSMATOPRO3 PCNA αSMATOPRO3 PCNA αSMATOPRO3 PCNA αSMATOPRO3 PCNA αSMATOPRO3 PCNA αSMATOPRO3 PCNA αSMATOPRO3 PCNA αSMATOPRO3 0 0 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 GFPPCNAαSMATOPRO3 200 200 150 150 100 100 50 50 0 0 50 50 40 40 30 30 20 20 10 10 0 0 RESULTS: MECHANISMS OF ACTION PERI-INFARCT INFARCT A B PERI-INFARCT INFARCT 1 WEEK 2 WEEKS 1 WEEK 2 WEEKS # ** BM-MNC ** ** PCNA+CAV1+/mm2 PCNA+CAV1+/mm2 ** ** ** ** ** PCNA CAV1TOPRO3 PCNA CAV1TOPRO3 PCNA CAV1TOPRO3 PCNA CAV1TOPRO3 CAV1+PCNA+ 1 WEEK 2 WEEKS 1 WEEK 2 WEEKS MSC GFPPCNACAV1TOPRO3 GFPPCNACAV1TOPRO3 GFPPCNACAV1TOPRO3 GFPPCNACAV1TOPRO3 ## ## ## ## ** ** BM-MNC ** PCNA+αSMA+ (MYOFIB)/mm2 PCNA+αSMA+ (MYOFIB)/mm2 ** MYOFIB (αSMA+) PCNA+ 1 WEEK 2 WEEKS 1 WEEK 2 WEEKS MSC BM-MNC PCNA+αSMA+ (SMC)/mm2 * PCNA+αSMA+ (SMC)/mm2 SMC (αSMA+) PCNA+ 1 WEEK 2 WEEKS 1 WEEK 2 WEEKS MSC BM-MNC MSC

  14. CONCLUSIONS • Treatment with bone marrow stem cells (BM-MNC or MSC) induced a long-lasting (3 months) improvement in cardiac function. Moreover, animals injected with MSC showed an increase of tissue metabolism, which was associated with a decreased infarct size and collagen content and a higher degree of revascularization. • The benefits observed after bone marrow stem cell transplantation were possibly due to paracrine mechanisms involved in angiogenesis and host cell proliferation and not through direct cell contribution.

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