Study of the synergy between PROK2 and CXCL12 in the chemotaxis of neuroblasts and endothelial cells in bioprinted tissue

Abstract

Prokineticin 2 (PROK2) and its PKR2 receptor are expressed in different tissues and, in nervous tissue, they are found in neurons, astrocytes, and microglia. In the central nervous system (CNS), one of the PROK2 physiological functions is the chemotaxis of neuroblasts from the neurogenic niche of the subventricular zone to the olfactory bulb. In a model of traumatic brain injury (TBI) in rodents, microglial cells secrete PROK2 stimulating neuroblast chemotaxis for injury. Also, in response to brain injuries, reactive astrocytes secrete the chemokine CXCL12, which acts via its CXCR4 receptor, expressed by migratory neuroblasts. In addition to neuroblast chemotaxis, both PROK2 and CXCL12 are chemoattractants for endothelial cells in the angiogenesis process. Although there are no reports in the literature, it is possible that the two chemokines, PROK2 and CXCL12, act in synergy, both in physiological and pathological situations, for example, after a CNS injury stimulating the attraction of neuroblasts and endothelial cells in an attempt to tissue regeneration. Currently, animal models are considered the gold standard for studies of the cellular and molecular processes of normal and pathological CNS functioning, including the blood-brain barrier (BBB) and the brain parenchyma. Although in vivo models have played a relevant role in advancing knowledge of the pathophysiology of diseases that affect the CNS, their usefulness is limited by differences between humans and rodents, which often prevent the direct transfer of results from animals to clinical practice in humans. Several in vitro experimental models have been used, but it is not possible to fully reproduce the complexity of brain tissue in many cases. The main limitation of 2D models is that they do not capture the 3D nature of fabrics. In this way, new tissue bioengineering techniques, mainly 3D bioprinting, can recreate the complexity of 3D microenvironments in vitro. This project aims to evaluate whether there is synergy between PROK2 and CXCL12 in attracting bioprinted neuroblasts (CXCR4+/PKR+ cells). As a perspective, the results will be used to develop a new approach for the production of bioprinted BBB since both CXCL12 and PROK2 are also chemotactic for endothelial cells. The use of a combination of PROK2+CXCL12 could be relevant for the development of a 3D printed model of BBB. (AU)