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.

Figure 1

Schematic representation of the key players in signaling pathways responsible for apoptotic cell death. (AIF= apoptosis inducing factor; Apaf= apoptosis protease activating factor; EndoG=endonuclease G).

Figure 2

Proposed mechanism involved in pharmacological preconditioning of skeletal myoblasts. Release of IL11 downstream of PI3K/Akt triggers autocrine and paracrine effects on the cells and involves ERK1/2 and STAT3 activation to promote cell survival.

Figure 3

Schematic representation of growth factor interaction with growth factor receptors on the cell surface to initiate PI3K/Akt pathway responsible for cell cycle progression, survival, and proliferation.