Biomimetic microenvironmental preconditioning enhance neuroprotective properties of human mesenchymal stem cells derived from Wharton's Jelly (WJ-MSCs)

Abstract

Tuning stem cells microenvironment in vitro may influence their regenerative properties. In this study Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) were encapsulated in 3D hydrogels derived from human fibrin (FB) or platelet lysate (PL) and the oxygen level was adjusted to physiological normoxia (5% O2). The influence of the type of the scaffold and physiological normoxia conditions was tested on the WJ-MSCs' survivability, proliferation, migratory potential, the level of expression of selected trophic factors, cytokines, and neural markers. Encapsulated WJ-MSCs revealed high survivability, stable proliferation rate, and ability to migrate out of the hydrogel and the up-regulated expression of all tested factors, as well as the increased expression of neural differentiation markers. Physiological normoxia stimulated proliferation of encapsulated WJ-MSCs and significantly enhanced their neuronal, but not glial, differentiation. Ex vivo studies with indirect co-culture of organotypic hippocampal slices and cell-hydrogel bio-constructs revealed strong neuroprotective effect of WJ-MSCs against neuronal death in the CA1 region of the rat hippocampus. This effect was potentiated further by FB scaffolds under 5% O2 conditions. Our results indicating significant effect of oxygen and 3D cytoarchitecture suggest the urgent need for further optimization of the microenvironmental conditions to improve therapeutical competence of the WJ-MSCs population.

Assessment of the Neuroprotective and Stemness Properties of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells under Variable (5% vs. 21%) Aerobic Conditions

“…The spontaneous differentiation of hWJ-MSCs towards neural lineages observed in the current study confirmed our previous findings [ 18 , 22 , 64 , 66 , 81 ]. Drela et al [ 18 ] described enhanced neuronal and glial differentiation of hWJ-MSCs as compared to hBM-MSCs cultured under 21% O 2 .…”

“…Despite the lack of cell–cell contact, hWJ-MSCs significantly reduced apoptosis of neurons in the hippocampal CA1 region via secretion of neuroprotective factors in both tested oxygen conditions (21% O 2 and 5% O 2 ). A similar neuroprotective effect independent of the oxygen concentration was also observed by Lech et al [ 81 ] for hWJ-MSCs cultured in 3D hydrogel scaffolds. Puig-Pijuan et al also proved potential neuroprotective and antioxidants effects of WJ-MSCs on hippocampal cultures [ 86 ].…”

“…This was in line with observed tendency of hWJ-MSCs neuronal lineage commitment in 21% O 2 and 3D hydrogel scaffolds, but only at the protein level. The transcriptomic data previously obtained by our group [ 81 ] proved that lowered oxygen together with 3D hydrogel scaffolds together enhance the expression of neuronal markers. These results clearly show the importance of setting up appropriate in vitro biomimetic conditions (3D and oxygen tension) to obtain conclusive results regarding hWJ-MSC differentiation potential.…”

“…In the case of BDNF, a decrease in secretion under 5% oxygen was observed, which is similar to the work of Majumdar et al [ 62 ]. In the work of Lech et al [ 81 ], the mRNA expression of BDNF in hWJ-MSCs cultured in 3D hydrogel scaffolds was also decreased under 5% O 2 in comparison to atmospheric conditions. However, due to the large differences between investigated donors, the dependence of the secretion of other factors on oxygen conditions could not be clarified.…”

Extracellular matrix derived from Wharton’s Jelly-derived mesenchymal stem cells promotes angiogenesis via integrin αVβ3/c-Myc/P300/VEGF

“…Studies have con rmed that CD-ECM could guide intricate cellular and tissue processes such as homeostasis, healing and regeneration [8]. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) is acquired from umbilical cord tissue with the ability to large amount of endogenous ECMs [9][10][11]. The ECM derived from WJ-MSCs contains abundant collagenic structural proteins, and other ECM components such as bronectin and laminin [12].…”