The Icarus Flight of Perinatal Stem and Renal Progenitor Cells Within Immune System

Abstract

Our immune system actively fights bacteria and viruses, and it must strike a delicate balance between over- and under-reaction, just like Daedalus and Icarus in Greek mythology, who could not escape their imprisonment by flying too high or too low. Both human amniotic epithelial and mesenchymal stromal cells and the conditioned medium generated from their culture exert multiple immunosuppressive activities. They have strong immunomodulatory properties that are influenced by the types and intensity of inflammatory stimuli present in the microenvironment. Notably, very recently, the immunomodulatory activity of human adult renal stem/progenitor cells (ARPCs) has been discovered. ARPCs cause a decrease in Tregs and CD3⁺ CD4^- CD8^- (DN) T cells in the early stages of inflammation, encouraging inflammation, and an increase in the late stages of inflammation, favoring inflammation quenching. If the inflammatory trigger continues, however, ARPCs cause a further increase in DN T cells to avoid the development of a harmful inflammatory state. As in the flight of Daedalus and Icarus, who could not fly too high or too low to not destroy their wings by the heat of the sun or the humidity of the sea, in response to an inflammatory environment, stem cells seem to behave by paying attention to regulating T cells in the balance between immune tolerance and autoimmunity. Recognizing the existence of both suppressive and stimulatory properties, and the mechanisms that underpin the duality of immune reaction, will aid in the development of active immunotherapeutic approaches that manipulate the immune system to achieve therapeutic benefit.

Keywords: T cells; immune system; immunomodulation; inflammatory response; perinatal stem cells; renal stem cells; stem cells.

Figure 1

The canonical pathway of ADO production initiates with CD39, an ecto- diphosphohydrolase responsible for hydrolyzation into mono- or di-phosphate nucleotide which are suddenly converted into soluble ADO by CD73. CD39 and CD73 can be present on the same cell or in close proximity when two cellular elements are adjacent. Interestingly, hAEC has been recently proved to constitutively expressed both canonical ecto-enzymes on membrane surface. However, such “canonical” way is not the sole molecular pathway responsible extracellular ADO production. Another “alternative” pathway has been described where nicotinamide adenine dinucleotide (NAD⁺), rather than ATP, is the initiating factor for ADO production (and relative immune cell modulation). NAD can be actively secreted across cell membrane and trigger a cascade of extracellular signals, starting with CD38 resulting in soluble ADPR. CD38, another membrane ecto-nucleotidase, lends ADPR over to CD203a, a surface nucleotide pyrophosphatase/phosphodiesterase 1, that generate mono-phosphate adenosine (AMP). Similarly to “classical” pathway, AMP generated in the “alternative” cascade is converted into ADO by CD73, the point of contact for the two canonical and alternative pathways.

Figure 2

(A) Following a renal damage ARPCs detect the insult by the binding of Pathogen Associated Molecular Patterns (PAMPs), such as lipoteichoic acid (LTA), or damage-associated molecular patterns (DAMPs) on the Toll-like receptor 2 (TLR2). ARPCs then inhibhit the Treg and the double negative (DN) T cells through paracrine mediators as PAI1, CXCL1, GM-CSF, and MCP1 to favor the initial phase of inflammation. (B) ARPCs can mediate immunomodulation and affect inflammatory state. The physiological response to tissue damage can be divided into three phases: inflammatory, reparative, and remodeling. During this process, inflammatory status (defined as the types and concentrations of cytokines and cells of the immune system present) changes considerably: proinflammatory influences (red dashed line) are dominant in the inflammatory, infection-fighting phase and diminish in the reparative and remodeling phases that follow, which allows wound healing. In the context of the intensity of the immune response (right vertical axis), the inflammatory response (red dashed line) fluctuates during the wound-healing process. Such changes in inflammation substantially alter the effects of mesenchymal stem cells (MSC)-meditated immunomodulation, which results in a variable correlation between the intensity of inflammation and efficacy of MSC treatment (solid black line). Such changes in inflammation are also affected by ARPC-meditated immunomodulation. ARPCs cause DN T cell decrease at the initial phase, promoting inflammation, and DN T cell increase in the late inflammation stages, favoring the inflammation quenching.