Mesenchymal Stromal Cells: Potential for Cardiovascular Repair

Disusun oleh: Ardhan Prahara Putra 0610710017

Pembimbing : Prof. Dr. dr. Djanggan Sargowo, Sp.PD, Sp.JP(K),FIHA, FAAC, FCAPC, FESC, FASCC

INTRODUCTION
Major causes of morbidity and mortality in Western community : Ischemic heart disease congestive heart failure
Heart failure: end result of pathological remodeling

cardiomyocyte death and loss of myocardial cell mass

Conventional management for HF replace lost cardiomyocyte mass or myocardial scar hearts own limited capacity for self-regeneration New management gene,GF,& cell-basedtherapy

Cellular therapy - preklinik in vitro & in vivo - clinical trial of myocardial infarction/ischemia & HF Cells - embryonic cells - adult-derived cells
Investigated to repair cardiac & vascular

OVERVIEW OF CELLULAR THERAPY FOR HEART DISEASE

Objective highly dependent on underlying disease myocardial ischemia, cardiac dysfunction, or a combination of the two Cell transplantation effective (a) provide a renewable source of proliferating, functional cardiomyocytes and (b) contribute to the development of a network of blood vessels to support and nourish these newly formed cardiomyocytes and the surrounding, ischemic myocardium

 Various stem, progenitor, and mature cell types have exhibited a capacity to influence these mechanisms in vivo Such as : Unfractionated bone marrow cells (BMCs) and mononuclear cells (BMMNCs), MSCs, hematopoietic stem cells, endothelial progenitor cells (EPCs), skeletal myoblasts, cardiac progenitor cells, fetal car- diomyocytes, and embryonic stem cells Controversy still surrounds all of the cell types scrutinized for cardiovascular application : optimal cell type, dose, mode of administration, mechanism of action, safety, and efficacy

Lessons from Studies Using Unfractionated Bone Marrow

Review of approximately 700 patients receiving intracoronary bone marrow (BM) therapy for acute MI demonstrated a modest but significant increase in left ventricular ejection fraction (EF) and reduction in infarct size and left ventricular end-systolic volume. These improvements were greatest in patients with lower EF ( 45%) and when cells were administered between days 5 and 7 after index MI. Although meta-analysis results have been encouraging, there has been a discrepancy between outcomes of individual trials.

MESENCHYMAL STROMAL CELLS: BASIC PRINCIPLES

Multipotent MSCs are rare, nonhematopoietic cells of mesodermal and neuroectodermal derivation that exist in a number of postnatal organs and connective tissues, most notably BM, but also gut, lung, liver, adipose, dental pulp, and periodontal ligament Although MSCs have gained rapidly increasing attention as a therapeutic tool for tissue repair, their study has been plagued by nonuniformity relating to the techniques used for their isolation, culture, and characterization, as well as their nomenclature

Traditional Isolation of MSCs

Traditional isolation of MSCs from BM has been based on simple density gradient separation of mononuclear cells and subsequent culture in tissue culture plastic. The mesenchymal subfraction is adherent to plastic and therefore easily separated from nonadherent hematopoietic cells. Under appropriate conditions, the adherent cells form colonies of varied morphologies (colony-forming unitsfibroblast [CFU-F] cells) over 714 days

Alternative Isolation Strategies

Immunoselection describes the isolation of highly purified mesenchymal precursor cells based on their reaction with spe- cific monoclonal antibodies that have been developed by im- munizing mice with human mesenchymal lineage precursors. Combinations of different monoclonal

 Mesenchymal stromal cells have a number of attractive characteristics, including (a) the ease with which they can be cultured to the high numbers needed for transplantation, (b) apparent potential for mediating both myocardial and vascular repair, and (c) immunoregulatory properties, which may enable their use as an allogeneic treatment.

MECHANISMS OF CARDIOVASCULAR REPAIR

Cardiac Regeneration: Evidence for Transdifferentiation The ultimate objective for myocardial cellular transplantation is for donor cells to engraft in the recipient tissue and ultimately differentiate into new, functional cardiomyocytes and vascular cells (smooth muscle and endothelial cells). This is especially the case given the hearts limited capacity for self-regenera- tion and the central role that cardiomyocyte death and re- placement fibrosis play in contributing to the development of heart failure

 Cardiac Repair: Paracrine Mechanisms The variable observations relating to cell transdifferentiation have prompted a rethinking of the mechanisms that account for the functional benefits observed in studies of cardiac cell therapy. Increasingly, it is believed that current cell therapies assist the heart predominantly by facilitating endogenous repair processes, rather than through actual regeneration of lost cardiac and vascular cells. Paracrine actions may underlie much of this reparative potential, including the capacity for cell transplantation to induce neovascularization, reduce infarct size and scar formation, and improve myocardial contractility

OPTIMIZING THE REPARATIVE BIOLOGY OF MSCs

The uncertainties surrounding the mechanistic action of stem cells in the diseased heart have resulted in the rapid growth of niche areas in the field of cellular research. Novel strategies are being developed to label cells either directly (e.g., with radio-nuclides or paramagnetic agents) or indirectly, by transfection with reporter genes, so that they can be serially imaged and tracked in vivo to determine their fate. Noninvasive imaging modalities that are being evaluated include optical imaging with bioluminescence and fluorescence, single-photon emission computed tomography, positron emission tomography, and magnetic resonance imaging (MRI)

PROGRESSING TO CLINICAL APPLICATION

The shortcomings of autologous MSC therapy include the time required to culture the cells to adequate numbers and the un- predictable recovery of multipotent stem cells from BM, espe- cially in elderly, unhealthy patients. The ideal resolution to these obstacles is the provision of allogeneic, off-the- shelf or ready-to-use cells that are obtained from healthy, young donors

Myocardial Delivery of Cells

Systemic Delivery. It is well known that hematopoietic cells and endothelial progenitor cells can be mobilized from BM by growth factors. Although there is recent evidence in rats to show the mobilization of BM MSCs into the peripheral circulation after hypoxic insult, it is not yet clear whether human MSCs respond significantly to growth factor administration

 Intracoronary Arterial Infusion. Selective intracoronary ad- ministration of cells achieves higher first-pass delivery to the heart than systemic therapy. The intracoronary route has been used safely and effectively for the infusion of unfractionated BM and peripheral blood-derived cells in clinical trials of acute MI post-MI cardiomyopathy chronic ischemic heart disease and nonischemic cardiomyopathy. Cells are typically injected through the central lumen of an over-the-wire balloon catheter during transient balloon inflations to stop coronary blood flow and increase cell exposure to the microcirculation and myocardium

 Intramyocardial Injection. Unlike intravascular infusion, direct intramyocardial injection targets specific regions of myocardium without relying on the upregulation of inflammatory signals to assist transvascular cell migration and tissue invasion. Preclinical results indicate that direct MSC injection may result in less noncardiac entrapment of cells than intracoronary and i.v. infusion. Moreover, myocardial cell retention may also be higher, culminating in greater benefit to cardiac function. This delivery approach appears well suited to larger and adherent cell types (e.g., MSCs), as well as to chronic myocardial disease, such as chronic ischemia or scarred myocardium from old infarction. Direct injection can either be (a) transepicardial during open chest surgery or via the coronary venous system or (b) transendocardial by percutaneous catheter-based techniques. The invasiveness of open transepicardial injection restricts its clinical use to patients undergoing sternotomy for other cardiac surgery, such as coronary artery bypass surgery

CONCLUSION

There is now a large body of preclinical evidence supporting the potential for a variety of cell types to facilitate cardiac and vascular repair. Currently, adult or postnatal tissue-derived cells appear limited in their capacity to achieve true replacement of damaged and/or dead cardiomyocytes, and their beneficial effects appear to be predominantly reparative, through indirect or paracrine effects on endogenous cells. Mesenchymal stromal cells from bone marrow and other tissues are an attractive candidate for cardiovascular therapy, largely because of their capacity for facilitating both vascular and myocardial repair and also because it is anticipated that they may be used allogeneically, obviating some of the obstacles inherent in autologous cell transplantation

THANK YOU