Instructing cells with programmable peptide DNA hybrids

Abstract

The native extracellular matrix is a space in which signals can be displayed dynamically and reversibly, positioned with nanoscale precision, and combined synergistically to control cell function. Here we describe a molecular system that can be programmed to control these three characteristics. In this approach we immobilize peptide-DNA (P-DNA) molecules on a surface through complementary DNA tethers directing cells to adhere and spread reversibly over multiple cycles. The DNA can also serve as a molecular ruler to control the distance-dependent synergy between two peptides. Finally, we use two orthogonal DNA handles to regulate two different bioactive signals, with the ability to independently up- or downregulate each over time. This enabled us to discover that neural stem cells, derived from the murine spinal cord and organized as neurospheres, can be triggered to migrate out in response to an exogenous signal but then regroup into a neurosphere as the signal is removed.

The microvascular extracellular matrix in brains with Alzheimer’s disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA)

“…In the present study, we found that laminin was significantly lower in lysates of MV isolated from high ADNC vs. not ADNC brains. Our data are based on what is generally considered a pan laminin antibody [47,48], but few prior studies have specifically examined laminin in the BBB with neurodegeneration. Early work reported an increase in punctate deposits of α1 and γ1 laminin chains in plaques of Aβ and in astrocytes of human brain parenchyma [49].…”

Engineering Hydrogel Microenvironments to Recapitulate the Stem Cell Niche

“…Surfaces initially presenting cell-adhesive RGD peptides could be rendered nonadhesive by addition of a control peptide possessing a stronger host-guest binding partner (60). Other self-assembly driven approaches have used complementary leucine zipper peptides (62) and complementary DNA strands (63,64) to achieve dynamic control over ligand presentation dynamics.…”

“…Recent efforts have been directed at incorporating dynamic mechanisms of growth factor tethering to temporally control presentation, including strategies employing supramolecular host-guest interactions (85) and enzymatic methods (86). To decrease costs associated with the use of full-length growth factors, small-peptide mimics capable of initiating growth factor signaling have been incorporated into several types of hydrogels (64,(87)(88)(89). Alternative methods for localizing cell-secreted factors have taken a more biomimetic approach, incorporating charged polysaccharides like heparan sulfate to sequester growth factors (90) or peptide sequences that bind and retain secreted ECM proteins (91).…”

Multivalent Clustering of Adhesion Ligands in Nanofiber-Nanoparticle Composites

“…For instance, the PHSRN sequence within fibronectin synergizes with RGD in a distance-dependent manner. [8][9] Different approaches have been developed to control ligand positioning and inter-ligand distances, including their conjugation onto amphiphilic [10][11][12][13] and PEGylated constructs, 14,15 oligopeptide backbones, [16][17][18] DNA constructs [19][20][21] or the functionalization of titanium surfaces to display distinct bioactive motifs in a chemically-controlled fashion. 22 The use of self-assembling peptide amphiphiles (PAs), which consist of a short peptide sequence linked to a hydrophobic alkyl tail, has been particularly promising in engineering bioactive artificial scaffolds for cells.…”