Hematopoietic Progenitor and Stem Cells Circulate by Surfing on Intracellular Ca2+ Waves: A Novel Target for Cell-based Therapy and Anti-cancer Treatment?

Francesco      Moccia; Elisa      Bonetti; Silvia      Dragoni; Jacopo      Fontana; Francesco      Lodola; Roberto      Berra Romani; Umberto      Laforenza; Vittorio      Rosti; Franco      Tanzi

Abstract

Hematopoietic progenitor and stem cells (HPSCs) have been employed in cell-based therapy (CBT) to promote neovascularisation and regeneration of ischemic organs, such as heart and limbs. Furthermore, endothelial progenitor cells (EPCs) may favour tumour growth and adverse vascular targeting treatment by incorporating into neovessels. CBT is hampered by the paucity of HPSCs harvested from peripheral blood and suffers from several pitfalls, including the differentiation outcome of transplanted cells and low percentage of engrafted cells. Therefore, CBT will benefit of a better understanding of the signal transduction pathway(s) which drive(s) HPSC homing, proliferation and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to combat tumoral neovascularisation. The elevation in intracellular Ca2+ concentration is the key signal in the regulation of cellular motility, replication, and differentiation. Intracellular Ca2+ waves regulate cytoskeleton re-organisation and disassembly at focal adhesions, thus stimulating migration and substrate adhesion, and induce DNA transcription by recruiting Ca2+-sensitive transcription factors. However, the Ca2+ signalling toolkit which underlies Ca2+ release from intracellular stores and Ca2+ entry across the plasmalemma in HPSCs is still unclear. Our recent work has shown that the so-called store-operated Ca2+ entry stimulates EPC growth. Unravelling the mechanisms guiding HPSC behaviour might supply the biological bases required to improve CBT. For instance, genetic manipulation of the Ca2+ signalling machinery (such as transfer of genes encoding for the Ca2+ channels involved in EPC proliferation) could provide a novel approach to increase the extent of limb neovascularisation and regeneration of damaged hearts.

Keywords: Ca2+ signalling; cell-based therapy; cyclic ADP-ribose; endothelial progenitor cells; gene-based therapy; hematopoietic stem cells; inositol-1, 4, 5-trisphosphate; stromal derived factor-1α; store-operated Ca2+ entry; vascular endothelial growth factor