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MANUEL Mª MAZO VEGA

U n i v e r s i d a d d e N a v a r r a. 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. Cardiovascular diseases: First cause of mortality

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MANUEL Mª MAZO VEGA

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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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