Human cardiomyocyte-derived exosomes induce cardiac gene expressions in mesenchymal stromal cells within 3D hyaluronic acid hydrogels and in dose-dependent manner

Abstract

Accomplishing a reliable lineage-specific differentiation of stem cells is vital in tissue engineering applications, however, this need remained unmet. Extracellular nanovesicles (particularly exosomes) have previously been shown to have this potential owing to their rich biochemical content including proteins, nucleic acids and metabolites. In this work, the potential of human cardiomyocytes-derived exosomes to induce in vitro cardiac gene expressions in human mesenchymal stem cells (hMSCs) was evaluated. Cardiac exosomes (CExo) were integrated with hyaluronic acid (HA) hydrogel, which was functionalized with tyramine (HA-Tyr) to enable the development of 3D (three dimensional), robust and bioactive hybrid cell culture construct through oxidative coupling. In HA-Tyr/CExo 3D hybrid hydrogels, hMSCs exhibited good viability and proliferation behaviours. Real time quantitative polymerase chain reaction (RT-qPCR) results demonstrated that cells incubated within HA-Tyr/CExo expressed early cardiac progenitor cell markers (GATA4, Nkx2.5 and Tbx5), but not cTnT, which is expressed in the late stages of cardiac differentiation and development. The expressions of cardiac genes were remarkably increased with increasing CExo concentration, signifying a dose-dependent induction of hMSCs. This report, to some extent, explains the potential of tissue-specific exosomes to induce lineage-specific differentiation. However, the strategy requires further mechanistic explanations so that it can be utilized in translational medicine.

Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

“…In addition, HA is widely present in connective tissues, and studies have indicated that HA hydrogels can provide sites for cell proliferation and differentiation; therefore, HA is widely used in tissue repair and reconstruction applications [ 84 , 85 ]. Burak Derkus [ 86 ] used HA hydrogels loaded with human cardiomyocyte-derived EVs and finds that they can induce the expression of heart-related genes in MSC.…”

“… [ 97 ] HA-tyramine (HA-Tyr) human cardiomyocyte 50 ​nm 5 days 3% HA-Tyr: retained almost half of EVs in the first 2 days, while the cumulative release was found until nearly 5 days. [ 86 ] Self-assembling peptides (SAPs) BMSC 120.1 ​± ​55.4 ​nm 168 ​h The release rate of EVs was dose-dependently accelerated in the presence of MMP2 compared to the blank group. [ 23 ] Atom transfer radical polymerization (ATRP) nonactivated macrophages J774A.1 30–150 ​nm up to one month The monomer-to-crosslinker ratio (molar ratio) and the crosslinking density of the polymer networks both affect the release of EVs.…”

Manipulating macrophage polarization with nanoparticles to control metastatic behavior in heterotypic breast cancer micro-tissues via exosome signaling

“…Exosomes were isolated from polarized (M1, M2, PdNPsinduced) and non-polarized macrophages (M0), using a previously described protocol, which has been successfully applied in various studies. [29][30][31] Initially, serum-free conditioned media (CM) were collected from different macrophage groups: (i) unpolarized (M0), (ii) M1 induced by LPS (200 ng ml −1 ) and IFN-γ (20 ng ml −1 ), (iii) M2 induced by IL-10 (20 ng ml −1 ), and (iv) M1-like induced by PdNPs (50 μg ml −1 ). The CM was then subjected to a series of centrifugation steps at 300g (5 min), 3000g (15 min), and 10 000g (15 min) at 4 °C.…”

Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease

“…Copyright 2019 Royal Society of Chemistry. Adapted with permission under a creative commons CC-BY license 4.0 from ref . Published 2021 by Springer Nature.…”

“…Mesenchymal stem cell (MSC) exosomes are paracrine factors in stem cells for cardiac regeneration . Human umbilical MSC exosomes were encapsulated in a functional peptide hydrogel for cardiac repair, and a three-dimensional hyaluronic acid hydrogel was used for loading of human cardiomyocyte-derived exosomes . There is also an injectable hydrogel to repair the injured heart …”