Strategies to promote donor cell survival: Combining preconditioning approach with stem cell transplantation

Abstract

Stem cell transplantation has emerged as a potential modality in cardiovascular therapeutics due to their inherent characteristics of self-renewal, unlimited capacity for proliferation and ability to cross lineage restrictions and adopt different phenotypes. Constrained by extensive death in the unfriendly milieu of ischemic myocardium, the results of heart cell therapy in experimental animal models as well as clinical studies have been less than optimal. Several factors which play a role in early cell death after engraftment in the ischemic myocardium include; absence of survival factors in the transplanted heart, disruption of cell-cell interaction coupled with loss of survival signals from matrix attachments, insufficient vascular supply and elaboration of inflammatory cytokines resulting from ischemia and/or cell death. This article reviews various signaling pathways involved in triggering highly complex forms of cell death and provides critical appreciation of different novel anti-death strategies developed from the knowledge gained from using an ischemic preconditioning approach. The use of pharmacological preconditioning for up-regulation of pro-survival proteins and cardiogenic markers in the transplanted stem cells will be discussed. An overview of heart cell therapyDuring the last decade, widespread experimental studies in animal models and clinical studies have shown the safety, feasibility and efficacy of cell based therapies for myocardial regeneration. Starting with the use of unipotent myogenic cells including skeletal muscle derived stem cells and cardiomyocytes, heart cell therapy has progressed to assess the feasibility of multipotent and pluripotent stem cells for cardiac repair 1,2 . Despite recent reports for their successful cardiomyogenic differentiation in vitro 3 , failure of skeletal myoblasts to electromechanically integrate and synchronously contract with the host myocytes post engraftment have restricted their use as the choice donor cells in clinical settings 4 . Similarly, cardiomyocytes are an excellent option for use as donor cells but their limited availability remains an issue of concern in clinical application 5,6 . Engraftment of non-myogenic fibroblasts and smooth muscle cells with contractility characteristics different from cardiomyocytes have also been shown to improve cardiac function 7,8 . Nevertheless, a repertoire of stem and progenitor cells in the bone marrow with differing plasticity and differentiation potentials have emerged as the most extensively studied cells for their myocardial regenerative potential in experimental animals and clinical studies 9,10 . In case of bone marrow derived stem cell engraftment, the mainstay of mechanisms for cardiac repair is #Corresponding Author: Muhammad Ashraf, Ph.D, Department of Pathology and Laboratory Medicine, 231-Albert Sabin Way, University of Cincinnati, OH-45267-0529, USA. Fax:1-513-558-0807, E-mail:E-mail: muhammad.ashraf@uc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has bee...

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

“…However, most ransplanted stem cells undergo apoptosis in the harsh microenvironment with poor blood and oxygen supply in the infarct zone (Haider and Ashraf, 2008). Therefore, protection of stem cells from apoptosis is crucial for a successful cell therapy.…”

“…Overexpression of pro-survival molecules including Akt (Mangi et al, 2003), Pim-1 (Fischer et al, 2009), Bcl-2 (Li et al, 2007) and stem cell factor (SCF) (Fazel et al, 2008) prevented donor cells from apoptosis. At the same time, pharmacological preconditioning with growth factors and cytokines can also improve the survival of transplanted cells (Haider and Ashraf, 2008).…”

14S,21R-dihydroxy-docosahexaenoic Acid Treatment Enhances Mesenchymal Stem Cell Amelioration of Renal Ischemia/Reperfusion Injury

“…B one marrow mesenchymal stem cells (MSCs) have shown potential for improving the treatment of several incurable diseases through their ability to self-renew and differentiate into mesenchymal and non-mesenchymal cells [1][2][3][4]. In particular, MSCs can ameliorate renal ischemia/ reperfusion (I/R) injury [5][6][7][8][9][10].…”

“…IGF-1 blocks not only the early onset of apoptosis, but also inflammation and accompanying tissue injury [26]. Although MSCs possess the capability to ameliorate acute kidney injury, the low viability of transplanted cells in I/R injured organs remains an important limitation for MSC therapy [2,27]. Reactive oxygen species (ROS) and inflammatory cytokines generated in I/R are the probable source of damage to the grafted MSCs [8,20].…”

“…Reactive oxygen species (ROS) and inflammatory cytokines generated in I/R are the probable source of damage to the grafted MSCs [8,20]. Several remedial approaches have been recommended to overcome MSC apoptosis [2], including ischemic or cytokine preconditioning and ex vivo genetic modification of stem cells. For example, melatonin increases survival of MSCs and accelerates kidney recovery from acute kidney injury [8].…”