Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

Abstract

Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.

Fig. 1

Therapeutic potential of stem cells and supposed effects of purinergic signaling. Stem cells of diverse origins, such as from adipose, cardiac, and neural tissues can restore and regenerate damaged tissues by secreting paracrine factors including purines and pyrimidines. ATP and adenosine interfere with tissue reactions following transplantation of stem cells of various origins in different ways. (1) Nucleotides modulate the immune response and thereby reduce inflammation processes and the risk of transplant rejection and cell death. (2) Purines and pyrimidines promote proliferation and differentiation of transplanted and endogenous stem cells by providing adequate stem cell niches. (3) Purines and pyrimidines promote migration of endogenous stem cells to the site of injury and increase engraftment rates. Stem cell types with therapeutic applications are human induced-pluripotent stem cells (hiPSC), human embryonic stem cells (hESC), adipose stem cells (ASC), cardiac stem cells (CSC), neural stem cells (NSC), bone marrow stem cells (BMSC), and umbilical cord stem cells (UCSC) which are transplanted by using stereotaxic surgery (SS), intracoronary retrograde infusion through coronary sinus (IRICS) or intravenous, intramyocardial, or intraperitoneal injection or lumbar puncture

Fig. 2

ATP-and adenosine-induced actions following cardiac ischemic insult. After myocardial injury following an ischemic insult, dead cells release ATP into the extracellular space. The released ATP stimulates P2Y14 receptors expressed by hematopoietic stem cells and possibly purinergic receptors on cardiac stem cells. NTPDases (ecto-nucleoside triphosphate diphosphohydrolases) dephosphorylate ATP via ADP to AMP, and 5-nucleotidase (5′-NT) catalyzes the hydrolysis of AMP to adenosine inducing anti-inflammatory responses by activation of A_2A and A_2B receptors, blocking neutrophil activation and migration