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Stem cell therapy and CV innovations What’s new ?. ON HEART TISSUE REENGINEERING ?. JC Chachques, MD PhD Georges Pompidou European Hospital Paris, France. Cardiac Bioassist - Cooperative Work Teams :. Olivier Schussler. Ottawa Heart Institut, Canada

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On heart tissue reengineering

Stem cell therapy and CV innovationsWhat’s new ?

ON HEART TISSUE REENGINEERING ?

JC Chachques, MD PhD

Georges Pompidou European Hospital

Paris, France


Cardiac bioassist cooperative work teams
Cardiac Bioassist - Cooperative WorkTeams :

  • Olivier Schussler. Ottawa Heart Institut, Canada

  • Carlos Semino. MIT + Barcelona Bioengineering Center

  • Jorge Genovese. Pittsburgh University, USA

  • Jorge Trainini. Avellaneda Hospital, Argentina


On heart tissue reengineering

HEART FAILURE IN EUROPE

  • Heart failure is the single biggest reason for acute hospital admission.

  • Around 30 million people in Europe have heart failure and its incidence is increasing.

  • More people are living to an old age, and more are surviving a heart attack but with damage to the heart.


Prevalence of heart failure in usa total population 305 millions
PREVALENCE of HEART FAILURE in USA (total population: 305 millions)


On heart tissue reengineering

Evidence for cardiomyocyte renewal in humansScience 2009; 324: 98-102 Frisen J. et al, Karolinska Institut, Stockholm, Sweden

  • Cardiomyocytes are generated also later in life ?

  • Carbon-14, generated by nuclear bomb tests during the Cold War, integrated into DNA allows to establish the age of cardiomyocytes in humans

  • Results: cardiomyocytes renew, with a gradual decrease from 1% turning over annually at age of 25, to 0.45% at age of 75

  • Fewer than 50% of cardiomyocytes are exchanged during a normal life span

  • Perspectives: development of therapeutic strategies aimed at stimulating this process in cardiac pathologies


Stem cell therapy and bioartificial myocardium

STEM CELL THERAPY andBIOARTIFICIAL MYOCARDIUM



On heart tissue reengineering

CELLS FOR MYOCARDIAL REGENERATION

  • Skeletal myoblasts

  • Bone marrow mononuclear cells

  • Bone marrow mesenchymal cells

  • Umbilical cord cells

  • Adipose tissue stroma cells

  • Mesothelial cells (from epiploon)

  • Menstrual blood endometrial cells

  • Stem cells from the testis

  • Embryonic cells (pluripotents)



On heart tissue reengineering

DEVELOPMENT OF

BIO-ARTIFICIAL MYOCARDIUM


On heart tissue reengineering

BACKGROUNDLimitations of Cellular Cardiomyoplasty

  • Cell bio-retention and engraftment within scar tissue is low

  • Mortality of implanted cells in ischemic myocardium is high

  • In ischemic heart disease the extracellular matrix is pathologically modified


Background 2 limitations of cellular cardiomyoplasty
BACKGROUND 2Limitations of Cellular Cardiomyoplasty

  • Implanted cells lack both mechanical synchronization and electrical integration, forming « islands of tissue »

    Questions and risks:

  • Excitation-contraction coupling?

  • Additional excitable cells?

  • Proarrhythmic?


Rationale for 3d cardiac tissue engineering
RATIONALE FOR 3D CARDIAC TISSUE ENGINEERING

  • The efficacy and arrhythmia occurrence of stem cell therapy depends on the surviving cell number as well as the delivery route of cells

  • A cell-seeded epicardial scaffolds should offert additional niches for cell homing without the risk of a proarrhythmogenic substrate

  • Allogeneic cells should be better tolerated in a matrix « niche environment »


On heart tissue reengineering

Heart extracellular matrixCell niche + cell homing

ml : muscular lacunae

cl : capillary lacunae


On heart tissue reengineering

COMPONENTS OF EXTRACELLULAR MATRIX IN HUMAN HEART

Collagen Type I (80%) : Ventricular chamber geometry, structural support

Collagen Type III (10%): Role in transduction of myocyte shortening during systole


On heart tissue reengineering

EXTRACELLULAR MATRIX IN ISCHEMIC HEART DISEASE

Collagen Type I :Decreases from 80% to 40%

Collagen Type III : Increases from 10% to 35%

RESULTS : Ventricular dilatation, systolic + diastolic dysfunctions


On heart tissue reengineering

COLLAGEN TYPE I MATRIX (Pangen 2, France)lyophilised, bovine collagen, 5 x 7 x 0.6 cm


On heart tissue reengineering

DEVELOPMENT OF ARTIFICIAL MYOCARDIUM

  • Collagen matrix (type I)

  • 3D and Biodegradable

  • Seeded with stem cells


On heart tissue reengineering

Collagen Matrix without cells seeded with cells


On heart tissue reengineering

Confocal Microscopy3D matrix + cells



On heart tissue reengineering

PRECLINICAL STUDIESPublished in Tissue Engineering 2007; 13:2681-7Cell-seeded collagen matrix - 2 Mo Follow-up


On heart tissue reengineering

BIOARTIFICIAL MYOCARDIUM « MAGNUM » Clinical Trial

M yocardial

A ssistance by

G rafting a

N ew bioartificial

U pgraded

M yocardium


On heart tissue reengineering

Rationale

Associate a procedure for myocardial and extracellular matrix regeneration, i.e.

Cellular cardiomyoplasty

+

Collagen scaffold grafting





On heart tissue reengineering

Functional Outcomes: 1 year follow-up

NYHA Class

p =0.005

Baseline

End FU


On heart tissue reengineering

LV Ejection Fraction (%)

p = 0.04

Echocardiographic

Study


On heart tissue reengineering

LV End Diastolic Volume (mL)

p = 0.03

Echocardiographic

Study


On heart tissue reengineering

LV FILLING

Doppler-derived mitral deceleration time (ms)

p = 0.01

DIASTOLIC FUNCTION


On heart tissue reengineering

Scar Area Thickness (mm)

p = 0.005

Echocardiographic Study


On heart tissue reengineering

Cellular CMP + MatrixRadioisotopic SPECT sestamibi studiesPreop 12 Months


On heart tissue reengineering

MAGNUM CLINICAL TRIALCONCLUSIONS

  • REDUCES THE SIZE AND FIBROSIS OF INFARCT SCARS

  • MINIMIZES GLOBAL VENTRICULAR DILATATION

  • IMPROVES DIASTOLIC FUNCTION

  • INCREASES MYOCARDIAL WALL THICKNESS

  • INDUCES MODULATION OF EXTRACELLULAR MATRIX


On heart tissue reengineering

MAGNUM CLINICAL TRIALCONCLUSIONS

  • The implanted matrix contributed to generate the “adequate niche” for native, transplanted and migrating stem cells


On heart tissue reengineering

FUTURE MATRIX IMPROVEMENTS

  • Crosslinking angiogenic growth factors

  • Prolong absorption delay by nanotechnologies and additional chemical - physical crosslinking

  • Stem cell preconditioning :

    hypoxic conditions (5%) during cultures

    in-vitro electrostimulation


Nature clin pract cardiovasc med 2009 6 240 9
Nature Clin Pract Cardiovasc Med 2009; 6: 240-9

Use of arginine-glycine-aspartic (RGD) acid adhesion peptides coupled with a new collagen scaffold to engineer a myocardium-like tissue graft

Schussler O, Coirault C, Louis-Tisserand M,

Chachques JC, Carpentier A, Lecarpentier Y


Frontiers in bioscience 2009 14 2996 3002
Frontiers in Bioscience. 2009; 14: 2996-3002

Cardiac pre-differentiation of human mesenchymal stem cells by electrostimulation

Genovese J, Spadaccio C, Schussler O,

Carpentier A, Chachques JC, Patel AN


Biomaterials 2009 30 1156 65
Biomaterials. 2009; 30: 1156-65

The effect of self-assembling peptide nanofiber scaffolds on mouse embryonic fibroblast implantation and proliferation

Degano IR, Quintana L, Semino C, et al.


On heart tissue reengineering

A prototypic synthetic extracellular matrix

  • Molecular designed material

  • Chemically defined

  • Synthetic process

  • Highly similarity to natural ECMs

  • structure: nano-scale fibers

  • self-assembling process

  • biologically permissive

  • non-competition with natural ECM

  • biodegradable

  • Mechanical properties for soft tissues

  • Modification control Building up properties

  • Transient scaffold

  • Injecting biological material


On heart tissue reengineering

A generic peptide scaffold network

Peptide nanofibers = 10-20 nm

Scaffold pore size = 50-200 nm