Effect of Chirality on Cell Spreading and Differentiation: From Chiral Molecules to Chiral Self-Assembly

Abstract

The influence of chirality on cell behavior is closely related with relevant biological events; however, many recent studies only focus on the apparent chiral influence of supramolecular nanofibers and ignore the respective effects of molecular chirality and supramolecular chirality in biological processes. Herein, the inherent molecular and supramolecular chiral effects on cell spreading and differentiation are studied. Left-handed nanofibers (referring to supramolecular chirality) assembled from L-amino acid derivatives can enhance cell spreading and proliferation compared to flat L-surfaces (referring to molecular chirality). However, compared to the D-surfaces (referring to molecular chirality), right-handed nanofibers (referring to supramolecular chirality) derived from D-amino acid suppress cell spreading and proliferation, overturning the conventional view that a fibrous morphology generally enhances cell adhesion. The results directly suggest that the amplification of chirality from chiral molecules to chiral assemblies significantly enhances the effect on regulated cell behavior by supramolecular helical handedness. Moreover, cell differentiation is found to be chirality dependent. It suggests that both the L-amino acid derivatives and the left-handed fibers facilitate osteogenic differentiation. This study provides useful insight into understanding the origin of chiral expression from the molecular to the macroscopic level in nature.

Chirality Effects in Peptide Assembly Structures

“…The results suggested that left-handed helical nanofibers formed by L -enantiomer increased cell adhesion and proliferation, while right-handed helical nanofibers formed by D -enantiomer had the opposite effects ( Liu et al, 2014 ). They also studied the difference of molecular and supramolecular chirality effects on cell differentiation and spreading, finding that amplification of chirality from chiral molecules to chiral assemblies dramatically increased the regulatory effect on cell behaviors by supramolecular helical handedness ( Dou et al, 2019 ). In addition, stem cell lineage diversification was shown to be directed by the chirality of fibrillar matrix.…”

“…Left-handed matrix formed by L -phenylalanine derivative was conductive for osteogenic lineage, while right-handed matrix formed by its D -analog was conductive for adipogenic lineage ( Wei et al, 2019 ). These different regulatory effects on cells were suggested to be closely related to stereospecific interactions between peptide assemblies and proteins ( Dou et al, 2019 , 2020 ; Wei et al, 2019 ; Sun et al, 2021 ).…”

Bio-inspired chiral self-assemblies promoted neuronal differentiation of retinal progenitor cells through activation of metabolic pathway

“…At 100 °C, the disappearance of CD signals at 230 nm and 270 nm suggested the disintegration of LPG and DPG self-assembled nanofibers, respectively. Two new weak CD peaks at 218 nm and 232 nm were ascribed to the molecular chirality from phenylalanine in LPG and DPG, respectively [ 14 , 18 ]. In the VCD spectra, the two groups of conversed peaks at 1655 cm −1 and 1630 cm −1 for LPG and DPG also demonstrated the inversion of the chiral structure from LPG to DPG nanofibers.…”

“…In this study, both non-assembled (N-DPG) and assembled molecules (DPG) were derived from d -amino acids. It has been reported that amplification of chirality from chiral molecules to chiral assemblies presented much more pronounced regulated cell behaviors [ 14 ]. Consistent with these studies, our data suggested that chiral assembled structure of DPG enhanced the effect of chiral amplification.…”

“…L/ d -phenylalanine methyl ester hydrochloride, 1,4-benzenedicarbonyl dichloride and diglycol were purchased from Shanghai Titian Scientific Co., Ltd and used without further purification L(D)PG molecule ( Fig. S1 ) was synthesized according to previous reference [ 14 ]. 1 H NMR (400 M Hz, DMSO‑ d 6 , δ): δ = 3.1 (m, 4H, CH 2 ), 3.4 (m, 16H, CH 2 ), 4.2 (q, 2H, OH), 4.7 (q, 2H, CH), 7.3 (m, 10H, Ar H), 7.8 (s, 4H, Ar H), 8.9 (d, 2H, NH) ppm.…”