Purinergic receptors and nucleotide processing ectoenzymes: Their roles in regulating mesenchymal stem cell functions

Abstract

Human mesenchymal stem cells (MSCs) are a rare population of non-hematopoietic stem cells with multilineage potential, originally identified in the bone marrow. Due to the lack of a single specific marker, MSCs can be recognized and isolated by a series of features such as plastic adherence, a panel of surface markers, the clonogenic and the differentiation abilities. The recognized role of MSCs in the regulation of hemopoiesis, in cell-degeneration protection and in the homeostasis of mesodermal tissues through their differentiation properties, justifies the current interest in identifying the biochemical signals produced by MSCs and their active crosstalk in tissue environments. Only recently have extracellular nucleotides (eNTPs) and their metabolites been included among the molecular signals produced by MSCs. These molecules are active on both ionotropic and metabotropic receptors present in most cell types. MSCs possess a significant display of these receptors and of nucleotide processing ectoenzymes on their plasma membrane. Thus, from their niche, MSCs give a significant contribution to the complex signaling network of eNTPs and its derivatives. Recent studies have demonstrated the multifaceted aspects of eNTP metabolism and their signal transduction in MSCs and revealed important roles in specifying differentiation lineages and modulating MSC physiology and communication with other cells. This review discusses the roles of eNTPs, their receptors and ectoenzymes, and the relevance of the signaling network and MSC functions, and also focuses on the importance of this emerging area of interest for future MSC-based cell therapies.

Keywords: ATP; Adenosine; Ectoenzymes; Mesenchymal stem cell; Purinergic receptors; cADPR; β-NAD.

Figure 1

Surface network of purinergic receptors and nucleotide ectoenzymes on mesenchymal stem cells. On the basis of the recent findings, all the purinergic receptors and ectoenzymes whose presence has been ascertained on mesenchymal stem cells through qPCR analyses and/or demonstration of a clear physiological function (see text for references) are shown. Furthermore, both ATP and β-NAD stimulation mechanisms and metabolisms are summarized as an example of the finely tuned extracellular balance between nucleotides and nucleosides and their pleiotropic effects. CX43 HC: CX43 hemichannels; Ade: Adenosine; NMP: Nicotinamide monophosphate; ER: Endoplasmic reticulum; RyR1,3: Ryanodine receptors 1 and 3.