Biomacromolecules. 2019 Sep 27. doi: 10.1021/acs.biomac.9b01096. [Epub ahead of print]

Iron Ion-Releasing Polypeptide Thermogel for Neuronal Differentiation of Mesenchymal Stem Cells.

Patel M, Lee HJ, Son S, Kim H, Kim J, Jeong B.

Abstract

A poly(ethylene glycol)-based thermogel can capture iron ion (Fe3+) through crown ether-like coordination bonds between the oxygen atom and metal ions, thus providing a sustained Fe3+-releasing system. Poly(ethylene glycol)-L-poly(alanine) thermogel was used in this study. The polypeptide forms a rather robust gel and the degradation products are neutral amino acid, which provides cyto-compatible neutral pH environments during the cell culture. During the heat-induced sol-to-gel transition at 37 oC, tonsil-derived mesenchymal stem cells (TMSCs) and iron ions were incorporated, leading to the formation of a three-dimensional matrix toward neuronal differentiation of the incorporated TMSCs. Initial concentration of the iron ions was varied between 0, 15, 30, and 60 mM. About 10 % of the loaded iron ions was released over 21 days, which continuously supplied iron ions to the cells. The incorporation of iron ions not only increased the gel modulus at 37 oC from 107 Pa to 680 Pa but also promoted cell aggregation with a significant secretion of the cell adhesion signal of FAK. Expression of biomarkers related to the neuronal differentiation of TMSCs including NFM, MAP2, GFAP, NURR1, NSE, and TUBB3 increased 4-35 fold at the mRNA level in the Fe3+-containing system compared to that of the system without Fe3+. Immunofluorescence studies also confirmed pronounced cell aggregation and significant increase in neuronal biomarkers at the protein level. This study suggests that an iron ion-releasing thermogelling system can be a promising injectable scaffold toward neuronal differentiation of stem cells.