Hematopoiesis Revolves Around the Primordial Evolutional Rhythm of Purinergic Signaling and Innate Immunity – A Journey to the Developmental Roots

Abstract

A cell's most significant existential task is to survive by ensuring proper metabolism, avoiding harmful stimuli, and adapting to changing environments. It explains why early evolutionary primordial signals and pathways remained active and regulate cell and tissue integrity. This requires energy supply and a balanced redox state. To meet these requirements, the universal intracellular energy transporter purine nucleotide-adenosine triphosphate (ATP) became an important signaling molecule and precursor of purinergic signaling after being released into extracellular space. Similarly, ancient proteins involved in intracellular metabolism gave rise to the third protein component (C3) of the complement cascade (ComC), a soluble arm of innate immunity. These pathways induce cytosol reactive oxygen (ROS) and reactive nitrogen species (RNS) that regulate the redox state of the cells. While low levels of ROS and RNS promote cell growth and differentiation, supra-physiological concentrations can lead to cell damage by pyroptosis. This balance explains the impact of purinergic signaling and innate immunity on cell metabolism, organogenesis, and tissue development. Subsequently, along with evolution, new regulatory cues emerge in the form of growth factors, cytokines, chemokines, and bioactive lipids. However, their expression is still modulated by both primordial signaling pathways. This review will focus on the data that purinergic signaling and innate immunity carry on their ancient developmental task in hematopoiesis and specification of hematopoietic stem/progenitor cells (HSPCs). Moreover, recent evidence shows both these regulatory pathways operate in a paracrine manner and inside HSPCs at the autocrine level. Graphical Abstract

Murine and Human-Purified very Small Embryonic-like Stem Cells (VSELs) Express Purinergic Receptors and Migrate to Extracellular ATP Gradient

“…Since VSELs express several P2X receptors, we tested their chemotactic response to eATP in the Transwell migration system and noticed that both human and murine VSELs migrated to the eATP gradient. Our data with HSPCs indicate that mainly P2X1, P2X3, P2X4, and P2X7 receptors regulate the chemotaxis of these cells to the eATP gradient [ 4 , 5 ]. Since all these receptors are also expressed on human UCB- and murine BM-derived VSELs, we plan to employ receptor-specific inhibitors and receptor-deficient mice to address their role in migrating VSELs to eATP gradient.…”

Murine and human-purified very small embryonic-like stem cells (VSELs) express purinergic receptors and migrate to extracellular ATP gradient.

“…The gaps in P2Y receptor numbering are because several receptors (P2Y3, P2Y5, P2Y7, P2Y8, P2Y9, and P2Y10) which have been cloned and were assigned as members of the P2Y receptor family have been removed from the list as purinergic ligands do not activate them. The P1 family activated by eAdo comprises four subtypes (A1, A2A, A2B, and A3) [1][2][3][4][5][6].…”

“…In addition to eATP and eAdo, other rare signaling extracellular nucleotides include some pyrimidines like UTP, UDP, or UDP-glucose. The P2X ionotropic channel receptor family stimulated exclusively by eATP consists of seven members (P2X1, 2, 3, 4, 5, 6, and 7), whereas the P2Y family responding to ATP, adenosine diphosphate (ADP), uridine triphosphate (UTP), uridine diphosphate (UDP), or UDP-glucose includes a total of eight receptors (P2Y1, 2, 4, 6, 11, 12, 13, and 14) [1][2][3][4][5][6]. The gaps in P2Y receptor numbering are because several receptors (P2Y3, P2Y5, P2Y7, P2Y8, P2Y9, and P2Y10) which have been cloned and were assigned as members of the P2Y receptor family have been removed from the list as purinergic ligands do not activate them.…”