cell therapy in cardiovascular diseases

Cell Therapy For Cardiovascular Diseases

Supervisors:Prof. Dr.

Ahmed Mohamed Zaghlol Darwish Professor of Cardiology

Faculty of Medicine Tanta University

Prof. Dr.

Magdy Mohamed El-MasryProfessor of Cardiology

Prof. Dr.

Samia Mahmoud Sharf El-deenProfessor of Cardiology

Definitions

Definition: Stem cells:• Cells with 3 major criteria:

Self renewal.Capacity of clonal expansion.Multipotant differentiation.

Definition: Progenitor cells:

Can differentiate into a specific type of cells. But, they are more specific than stem cells:

they are pushed to differentiate into their "target" cells.

Classification of cells according to their potency

Classification of cells according to their potency:

• Totipotent stem cells: Produce all types of tissue including placenta.Eg. Early embryonic cells.

• Pleuripotent stem cells :Produce all types of tissue except placenta.EG. (ESCs).

Classification of cells according to their potency:

• Multipotent stem cells:Produce cells of a closely related family .Eg. (HSCs) that differentiate to red blood

cells, white blood cells and platelets.

• Unipotent stem cells :Produce only one type of cells and have the

ability of self renewal.Eg. epidermal stem cells.

Classification of cells according to their source.

Classification of cells according to their source:

Embryonic Stem Cells. Bone Marrow–Derived Stem/Progenitor Cells:

Hematopoietic stem cells (HSCs). Mesenchymal (stromal) stem cells (MSCs). Endothelial progenitor cells.

Umbilical Cord Blood Cells. Resident cardiac stem/progenitor cells. Adipose-derived stem cells. Skeletal myoblasts.

Embryonic Stem Cells. Are isolated from the inner cell mass of the

blastocyst.

Bone Marrow–Derived Stem/ Progenitor Cells

Hematopoietic stem cells• Sources :

i. Umbilical cord blood (1 per 1 million nucleated cell).

ii. Adult bone marrow (1 per 3 million nucleated cell).

iii. Mobilized peripheral blood (1 per 6 million nucleated cell).

Capable of unlimited cell proliferation in bone marrow producing mature blood cells.

Mesenchymal (stromal) stem cells:• Present as a rare population of cells in bone

marrow (0.001% to 0.01% of the nucleated cells).

• Other sources of MSC including placenta, adipose tissue, cord blood and liver.

• They can be cloned and expanded in vitro more than 1 million-fold and retain the ability to differentiate to several cells of mesodermal origin.

Hematopoietic stem cells (HSCs). Mesenchymal (stromal) stem cells (MSCs).

Endothelial progenitor cells. Umbilical Cord Blood Cells. Resident cardiac stem/progenitor cells. Adipose-derived stem cells. Skeletal myoblasts.

Endothelial progenitor cells.• Cells can give rise to endothelial cells and

contribute to endothelial recovery and new capillary formation after ischemia.

• Sources of endothelial progenitor cells:i. Bone marrow-derived EPCs.ii. Non Bone marrow-derived EPCs: Which arise from Various tissues, including adipose tissue,

neuronal tissue, and the heart itself.

Umbilical Cord Blood Cells.• Perfect source for cell-based therapy as they

are rich in both stem and progenitor cells.

• No ethical limitations regarding its use.

• No risks to the mother or to the newborn in collecting the cells after labor.

• There are many public and private UCB banks worldwide with cells readily available for transplantation at the most optimal time.

Umbilical Cord Blood Cells.

Resident cardiac stem/progenitor cells. Adipose-derived stem cells. Skeletal myoblasts.

Resident cardiac stem/progenitor cells.

• Recently it was proven that adult heart is an organ with regeneration capacity.

• This regeneration capacity are likely due to presence of defined pool of resident progenitor cells.

• These cells are responsible for the normal turnover of cardiomyocytes during physiologic growth and aging.

Resident cardiac stem/ progenitor cells have 4 populations according to their cell marker:

1. Cardiac side population (SP) cells.2. c-kit positive cardiac stem cells.3. Sca-1 positive cardiac progenitor cells.4. Cardiosphere-derived cardiac stem

Resident cardiac stem/progenitor cells.

Umbilical Cord Blood Cells. Resident cardiac stem/progenitor cells.

Adipose-derived stem cells. Skeletal myoblasts.

Adipose-derived stem cells.

• Recent studies have suggested that stem cells are present within the adipose tissue.

• This Adipose-derived stem cells, like MSCs, have the ability to differentiate toward the osteogenic, adipogenic, myogenic, chondrogenic and neurogenic cells.

• The ease of access to fat and its abundance makes adipose tissue a potentially useful source of stem cells for clinical applications.

Umbilical Cord Blood Cells. Resident cardiac stem/progenitor cells. Adipose-derived stem cells.

Skeletal myoblasts.

Skeletal myoblasts.• Skeletal myoblasts were the first candidates for

cardiac repair.

• They are derived from skeletal muscles “satellite cells”.

• They are responsible for regeneration of damaged skeletal muscle after injury.

Methods Of Cell Delivery

• The ideal modality of cell delivery should have the following characteristics:

Safe with minimal complications.Easily performed.Cost benefit ratio within range.Applicable across a wide range of clinical

scenariosTargeting of the cells precisely in an adequate

cardiac environment.

1) Direct myocardial injection: The most accurate type of delivery that can be

achieved by direct visualization during thoracotomy.

Can be done either as an adjunct to CABG or as sole therapy.

• Disadvantages:Possible arrhythmogenicity.Need for concomitant open-heart surgery.Can’t be repeated if needed.

2) Transcatheter endomyocardial injection: Less invasive technique.

Electromechanical testing to confirm the presence of ischemic or dead myocardium should be done before cell delivery.

• Disadvantages:Complex procedure as electromechanical

map of the left ventricular chamber is required.

3) Intracoronary cell injection: Most popular mode of cell delivery especially

after AMI.

It can be performed at the same time of (PCI).

Disadvantages:Not suitable for all cell types as larger cells as MSCs may occlude the Microcirculation.

4) Intravenous injection: The simplest and least invasive delivery route and

produces minimal complications.

Can easily be repeated if necessary.

Disadvantage:low percentage of cells delivered.

5) Intramyocardial injection via coronary vein

The catheter can enter the coronary sinus directed by IVUS.

The needle is directed toward the myocardium through which cells and drugs can be injected.

The safety and feasibility of this new catheter approach needs to be investigated.

Mechanisms of Myocardial Repair

• Cell therapy seems to act through three mechanistic pathways:

i. Differentiation into cardiomyocytes.ii. Cell Fusion with host cardiomyocytes.iii. Paracrine effects.

I. Differentiation into cardiomyocytes

The cell differentiation to cardiomyocytes is influenced by:high level of circulating stem cells.Organ damage Signaling factors as G-CSF, VEGF. cell-to-cell contact with cardiomyocytes.

Doubt still exists if the trasdifferentiated cells can participate in the actively contractile myocardium.

II. Cell Fusion with host cardiomyocytes.

Myocardial regeneration could result from fusion of the transplanted stem cell with existing cardiac cells “hybrid cells”.

Donor cell genes may compensate for the lost genetic material from the host nucleus during ischemic injury.

III. Paracrine effects:

Implanted cells releases a number of local cytokines and growth factors as TNF-α, VEGF, IGF, Cardiotrophin-1.

These factors: I. Inhibit cardiomyocyte apoptosis.II. Enhance angiogenesis.III. Rescue injured myocytes.IV. Inhibit pathologic remodeling.

Cell Therapy for Acute Myocardial Infarction

Most of the clinical trials in the field of AMI used BMCs with Conflicting Results.

MSCs was used in one trail by Chen et al, With significant improvement of LVEF and LVEDd.

Further larger randomized trails is needed in this field.

Cell Therapy in End-stage Ischemic Heart Disease With no Further Revascularization

Options

The main therapeutic goal for these patients is to improve blood supply.

Most trials have been small phase 1 studies and shown improved perfusion and myocardial function.

Concerns were raised by observation that some patient developed an acute coronary syndrome and fatal myocardial infarction.

Cell Therapy For Ischemic Cardiomyopathy & Chronic

Heart Failure

In the field of heart failure results of initial attempts of cell therapy have been more heterogeneous.

Two main cells was involved in HF cell therapy trials:

Skeletal Myoblasts.Bone Marrow Cells.

Skeletal Myoblasts clinical trails:

In most trials, improvements of regional wall motion and global LVEF have been noted after myoblast injections.

However, myoblast injections increase the risk of ventricular arrhythmias in this patient, with unclear mechanisms.

Bone Marrow Cells clinical trails: In most BMCs trials showed improved cardiac

function with less complications compared with SKMB trials.

Cell Therapy For Pulmonary Arterial

Hypertension

One of the more recent applications of cell therapy with very limited clinical experience.

Role of cell therapy in PAH either: Contributing to blood vessel thickening

(remodeling) and blockage in PAH.Repair damaged blood vessels and restore

more normal blood flow in the lung.

Cell Therapy For Peripheral Vascular

disease

Cell therapy can induce new vessels formation by 2 mechanisms:i. Vasculogenic effect: by incorporation into

newly forming vessels.ii. Trophic effect: delivering angiogenic growth

factors.

Overall, clinical trials reported encouraging effect of cell therapy in this field.

Drawbacks to Cell Therapy in

Cardiovascular Diseases

Cellular therapy has both theoretical and reported safety concerns.

These adverse effects include:

1) Atherosclerosis:Neointimal hyperplasia due to excessive

accumulation of SMCs derived from donor cells.

2) Post-stenting Restenosis:Caused by differentiation of progenitor cells

into SMCs within the stented segment

3) G-CSF Induced Acute Coronary Syndromes:Possible due to increased CRP level might

induce plaque destabilization and rupture.

4) Arrhythmogenesis:A common adverse effect with SKMB

trafustion.May be due to the ability of myoblasts to fire

action potentials that may induce deleterious extrasystoles

5) Stem Cell Immunogenicity:Allogenic origin of cells has raised concern of

allograft rejection and the need for immunosuppressive agents.

6) Tumorigenesis:The pluripotency of ESCs may enhance

undefined growth in vivo, giving rise to teratomas.

7) Stem Cell Metastasis:Also transplanted ESCs can form teratomas in

distant sites such as the submandible and femur.

8) Ethical concerns: Regarding ESCs use as they are isolated from

the early embryo “destroying the embryo”

Thank you

cell therapy in cardiovascular diseases

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