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Stem Cells in cardiovascular diseases

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Presentation on theme: "Stem Cells in cardiovascular diseases"— Presentation transcript:

1 Stem Cells in cardiovascular diseases
Arshed A. Quyyumi MD; FRCP Professor of Medicine Division of Cardiology Emory University School of Medicine Atlanta, Georgia, USA

2 Disclosure of Financial Relationships
Grant/research support: National Institutes of Health, American Heart Association Eli Lilly, Novartis, Pfizer, Amorcyte, Biomarin, Forest Advisory Boards: Amorcyte, Endothelix, Novartis

3 Types of Stem Cells Embryonic stem cells – Pluripotent
Fetal and adult stem cells (e.g. mesenchymal cells) – Multipotent; capable of producing a small range of differentiated cell lineages appropriate to their location Adult progenitor cells (e.g. skeletal myoblasts and endothelial progenitor cells) – Unipotent; has the least differentiation potential Induced pluripotent stem cells (IPS)

4 Adult Bone Marrow Stem Cell Plasticity
Endothelial Progenitor Cells Neural cells Epidermal cells Blood cells Ectodermal Progenitor Cells Hematopoeitic cells Mesodermal Progenitor Cells Bone Marrow Stem Cells Myocytes (Skeletal) (Cardiac) Osteocytes, Chondrocytes Stromal or Mesenchymal MAPC Endodermal Progenitor Cells Hepatocytes Resident stem cells: Heart, skeletal muscle, Adipose tissue, brain, Lung etc.

5 Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003)
Endothelial cells Smooth muscle cells VEGF PDGF Hypoxia HIF-1 SDF-1 CXCR4 Figure 2: Molecular switches involved in the mobilization and recruitment of endothelial, lymphatic and hematopoietic stem and progenitor cells. Vascular trauma results in the plasma elevation of angiogenic factors, including VEGF-A and PLGF, that activate MMP-9. Activation of MMP-9 results in increased bioavailability of the stem cell–active cytokine, soluble Kit ligand (sKitL), enhancing the cycling and proliferation of hibernating VEGFR1+c-Kit+ HSCs, VEGFR3+ lymphatic and c-Kit+ VEGFR2+ vascular progenitors. Increased cycling of the stem cells results in localization of precursors to the vascular zone, setting the stage for mobilization to the peripheral circulation and homing to the neoangiogenic site. Comobilization of proangiogenic VEGFR1+ hematopoietic stem and progenitor cells may facilitate functional incorporation of VEGFR2+ EPCs into neovessels. In addition, Syk+ and SLP-76+ hematopoietic cells may convey signals for the separation of newly formed blood and lymphatic vessels. mKitL, membrane Kit ligand. Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003) Cerdani DJ Nat Med 2004

6 Human studies with cell therapy in cardiovascular diseases
Cell types: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Cord blood Skeletal myoblasts Mesenchymal stem cells Resident cardiac stem cells Adipose tissue progenitors Disease states: Acute MI, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization

7 Delivery options for stem cells
Intracoronary Coronary sinus Direct myocardial injection epicardial, endocardial), Intravenous Bone marrow mobilization Delivery options for stem cell transfer modalities to the heart. The red colored area represents apical lesion of the left ventricle by myocardial infarction. The balloon catheter is localized in the infarct-related artery and is placed above the border zone of the infarction. Blue and green arrows suggest the possible route of cell infusion and migration into the infarct. The 2 small figures depict the transendocardial and intramyocardial route of administration. RCA indicates right coronary artery; LAD, left anterior descending coronary artery; and CFX, circumflex artery. Delivery devices

8 Human studies with cell therapy in cardiovascular diseases
Cell types: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Cord blood Skeletal myoblasts Mesenchymal stem cells Resident cardiac stem cells Disease states: Acute MI, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization

9 Skeletal myoblasts Myoblasts derived from satellite cells in skeletal muscle With appropriate stimulus, satellite cells differentiate into muscle fibres Highly resistant to ischemia Do not contract spontaneously Do not differentiate into cardiomyocytes Orient towards cardiac stress reducing thinning and dilation Improve diastolic and systolic function Potential risk of fatal arrhythmia;

10 Human studies with cell therapy in cardiovascular diseases
Cell types: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Cord blood Skeletal myoblasts Mesenchymal stem cells Resident cardiac stem cells Adipose tissue progenitors Disease states: Acute MI, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization

11 Allogeneic Mesenchymal Stem Cells for Acute Myocardial Infarction
60 patients enrolled Baseline EF~50% Intravenous adult human MSCs (Provacel™, Osiris Therapeutics) given 1-10 days after infarct (vs. placebo) No increase in adverse events No difference in baseline EF LAD infarcts: MSC therapy: increase in EF at 3 (48.8 ± 11.9 vs 57.1 ± 8.2; P 0.02) and and 6 months (56.3 ± 8.7; P=0.05). Changes in EF in the placebo patients and the non-LAD groups were not significant Hare JM, et al., ACC Scientific Sessions 2007 (abstract) Zambrano, T, et al., Circulation. 2007;116:II_202. (abstract)

12 Human studies with cell therapy in cardiovascular diseases
Cell types: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Cord blood Skeletal myoblasts Mesenchymal stem cells Resident cardiac stem cells Disease states: Acute MI, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization

13 Human studies with cell therapy in cardiovascular diseases
Cell types: Endothelial progenitor cells: Bone marrow mononuclear cells, Bone marrow endothelial progenitors eg. CD34+, CD133+ etc Peripheral blood progenitors (ex vivo expansion) Cord blood Skeletal myoblasts Mesenchymal stem cells Resident cardiac stem cells Disease states: Acute MI, Heart failure with scar or hibernating myocardium, Chronic ischemia not amenable to conventional revascularization

14 Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure The NOGA Myostar injection catheter, with the needle in the extended position (insert). Biosense Webster Myostar/ NOGA catheter Perrin E Circulation 2003

15 Losordo D et al ACC 2009

16 Losordo D et al ACC 2009

17 Clinical trials with endothelial progenitor cells
Disease states: Acute MI, Heart failure with hibernating myocardium Myocardial ischemia and unrevascularizable disease Peripheral arterial disease

18 Potential mechanisms of benefit of bone marrow derived cells after myocardial infarction
Transdifferentiation to cardiomyocytes Attenuation of Remodelling Arteriogenesis or Angiogenesis Paracrine effects Cell fusion Reduction of apoptosis Promoting endogenous Cardiac stem cell function

19 More than 1200 patients with STEMI randomized
Improvement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow-derived cells (BMCs) More than 1200 patients with STEMI randomized Modest improvement in ejection fraction (EF 3%) Reduction in infarct size Reduction in end-systolic volume Comparison with pharmacological therapy post MI: Capricorn study (Carvedilol vs. placebo after AMI EF<40%): EF increased by 3.9% and end-systolic volume by 9.2 mls. Mortality reduced by 25%. Figure 2. Forest plot of unadjusted difference in mean (with 95% confidence intervals [CIs]) improvement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow–derived cells (BMCs) compared with controls. The figure shows the summary of cohort studies and randomized controlled trials (RCTs). Transplantation with BMCs resulted in a 3.66% (95% CI, 1.93% to 5.40%) increase in mean LVEF. The overall effect was statistically significant in favor of BMC therapy. AMI indicates acute myocardial infarction; CPCs, circulating progenitor cells; OMI, old myocardial infarction; and WMD, weighted mean difference. Enca Martin-Rendon Eur Heart J 2008; 29:1807 Abdel-Latif, A. et al. Arch Intern Med 2007;167: . Lipinski et al J Am Coll Cardiol; 2007;50:1761

20 Bone marrow CD34+ cell injection after STEMI (AMRS 1)
Emory University, Atlanta, GA ; Vanderbilt University, Nashville, TN; Lindner Center, Cincinnatti, Ohio; Texas Heart Institute Primary Objective Feasibility and safety of intra-coronary infusion of autologous CD34+ cells at three dose levels (5, 10, 15 million). Secondary Objective To assess the effect on cardiac function (MRI, echo) and infarct region perfusion (SPECT) . Assess mobility/homing (CXCR-4), viability and in vitro hematopoietic and precursor cell growth (CFU-G). Only study to investigate cell dose-response Largest dose of i.c. CD34+ cells given to date

21 Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI
Chest pain + STEMI Screening Echo EF <50% SPECT MRI Stenting + Usual medical Rx Day 1-9 Bone marrow harvest Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI Intracoronary cell product infusion Days 1-10 cell product Cell product concentration

22 ISOLEX is a trademark of Baxter International Inc.
Progenitor cell Therapeutics, NJ Sterility Pyrogenicity Ex vivo viability ISOLEX is a trademark of Baxter International Inc.

23 Paramagnetic CD34 Positive Cell Selection
Anti-CD34 mAb Paramagnetic bead SAM Ig antibody MNC Fraction Containing CD34+ Stem Cells Purified CD34+ Cells PR34+ Release Agent Slides 25 and 26. CD34 selection can only compete with the tumour depletion procedure if the purity of the product obtained is in excess of 99% (models to show this are included in this and other presentations). One obvious prerequisite for this approach to cell selection is that the tumour cells do not express the Cd34 antigen. In fact few cases of CD34 expression on non- haematological malignancies have been reported, but occasionally it has been observed. For example, it is known that some neuroblastoma cell lines can express markers normally associated with cells of haematological origin. CD34 antigen expression has been reported occasional neuroblastoma cell lines, but not on fresh tumour samples.

24 Volume reduction of CD34+ selected cells

25 Intracoronary cell therapy trial : bone marrow CD34+ cell injection post acute ST elevation MI (AMR 1) CD34+ cells are infused via the infarct related artery 6 to 9 days following successful coronary artery stenting.

26 Intracoronary bone marrow mononuclear cell injection after acute ST elevation MI
Chest pain + STEMI Screening Echo EF <50% SPECT MRI Stenting + Usual medical Rx Day 1-9 Bone marrow harvest Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRI Intracoronary cell product infusion Days 1-10 cell product Cell product concentration

27 Bone marrow CD34+ cell injection after STEMI (AMRS 1)
-5.7 mL vs mL +4% vs. +1% -10% vs. -3%

28 Bone marrow CD34+ cell injection after STEMI (AMRS 1)
Resting perfusion: SPECT total severity score Resting total severity score Control, 5 million cells = +13 10, 15 million cells = -256 (p=0.01)

29 Bone marrow CD34+ cell injection after STEMI (AMRS 1)
Intracoronary infusion of autologous bone marrow CD34+ cells during the repair phase after STEMI at higher doses than previously administered is safe, and may be associated with improved functional recovery from enhanced perfusion to the peri-infarct zone.

30 Bone marrow-derived cell therapy for AMI
Ongoing studies: Worldwide: Ten studies US: Bone marrow: Intracoronary administration TIME (n=120), (NHLBI), Late –TIME (n=87) (NHLBI), Minneapolis (n=60) CD34+ cells: AMRS (Amorcyte) Allogeneic Mesenchymal Precursor Cells n=25 Direct myocardial injection (Angioblast Systems) Mesenchymal Stem Cells (Provacel) Intravenous injection (Osiris)

31 Cell therapy trials in acute MI
Progenitor Cell Laboratory W. Robert Taylor M.D., PhD Diane Sutcliffe AMRS1 Sponsor: Amorcyte Inc. PI: Arshed Quyyumi MD Clinical sites: Emory University, Atlanta, GA Vanderbilt University, TN Douglas Vaughan MD Lindner Center, Ohio Dean Keriakis MD Texas Heart Institute Jim Willerson MD Core labs: Fabio Esteves MD James Galt PhD Stam Lerakis MD John Oshinski PhD Quyyumi Lab: Jonathan Murrow M.D. Mick Ozkor MD. Saurabh Dhawan M.D. Riyaz Patel M.D. Ayaz Rehman MD A. Konstantinos M.D. Salman Sher Yusuf Ahmed Irina Uphoff Ibhar Al-Mheid Nino Kavtaratze Hamid Syed Shawn Arshad Hematology/ Stem Cell Processing E. Waller M.D., PhD Sagar Lonial M.D. Kreton Mavromatis M.D. Ziyad Ghazzal M.D. Habib Samady M.D. Tanveer rab MD. Chandan Devireddy MD Henry Liberman MD Douglas Morris MD Emory Intereventional faculty


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