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Harnessing isomerization-mediated manipulation of nonspecific cell/matrix interactions to reversibly trigger and suspend stem cell differentiation.

ABSTRACT: Specific protein-cell and drug-cell interactions have been widely used to manipulate stem cell fate. Despite extensive studies, most current platforms cannot realize reversible manipulation of stem cell differentiation. In this work, we report a photodynamic zwitterionic hydrogel capable of reversibly triggering and suspending the differentiation process via manipulating nonspecific interactions between cultured stem cells and the hydrogel. The differentiation state of stem cells can be altered by exposing the hydrogel to a selected light program, while differentiation can be immediately suspended when near-infrared exposure converts the hydrogel into a purely zwitterionic form. While many other studies apply specific interactions to control stem cell fate, this work provides a completely different approach-allowing reversible, real-time and localized manipulation of stem cell fate choice via nonspecific interactions.

SUBMITTER: Bai T

PROVIDER: S-EPMC5518545 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Harnessing isomerization-mediated manipulation of nonspecific cell/matrix interactions to reversibly trigger and suspend stem cell differentiation.

Bai Tao T Sinclair Andrew A Sun Fang F Jain Priyesh P Hung Hsiang-Chieh HC Zhang Peng P Ella-Menye Jean-Rene JR Liu Wenguang W Jiang Shaoyi S

Chemical science 20151007 1

Specific protein-cell and drug-cell interactions have been widely used to manipulate stem cell fate. Despite extensive studies, most current platforms cannot realize reversible manipulation of stem cell differentiation. In this work, we report a photodynamic zwitterionic hydrogel capable of reversibly triggering and suspending the differentiation process via manipulating nonspecific interactions between cultured stem cells and the hydrogel. The differentiation state of stem ...[more]

PMID: 28791097

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Project description:Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., "eat-me" signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.

Project description:Extracellular vesicles (EVs), specifically exosomes, carry a cell-type dependent cargo that is transported to the recipient cell and translated in the presence of a required machinery. Differences in the cargo carried by the corneal and conjunctival-derived EVs could be the agent that triggers the transdifferentiation of these two cell populations. Therefore, this study investigates the role of EVs in triggering the plasticity of corneal and conjunctival epithelial cells and identifies prospective miRNA and genes responsible for maintaining ocular surface homeostasis. The EVs were extracted from the conditioned media (after starving) of corneal epithelial (hTCEpi) and conjunctival (HCjE-Gi) cell lines using ultracentrifugation. HCjE-Gi cells were cultured with hTCEpi-derived EVs and vice-versa. The EVs were characterized as exosomes using Nanosight and Flow cytometry. KRT3 and KRT12 were used as associated corneal markers, whereas KRT7 and KRT13 were used as associated conjunctival markers with ΔNp63 as a differentiation marker. Shift of these markers was an indication of transdifferentiation. The cargo of the extracted exosomes from both the cell types was explored using next-generation sequencing. The hTCEpi-derived EVs induced conjunctival epithelial cells to express the corneal-associated markers KRT3 and KRT12, losing their conjunctival phenotype at both the mRNA and protein level. Simultaneously, HCjE-Gi-derived EVs induced corneal epithelial cells to express the conjunctival associated markers KRT7 and KRT13, losing their corneal phenotype. This process of differentiation was accompanied by an intermediate step of cell de-differentiation showed by up-regulation in the expression of epithelial stem cell marker ΔNp63, also shown on the ex vivo human cadaveric donor corneas. miRNA molecules (total of 11 including precursor and mature) with significant differences in their relative abundance between the two populations (p < 0.05) were found and investigated. miR-9-5p expression was higher in HCjE-Gi cells and HCjE-Gi-derived EVs when compared to hTCEpi cells and hTCEPi-derived EVs (p < 0.001). The results suggest that EVs released by the two cell types have the ability to influence the transdifferentiation of human conjunctival and corneal epithelial cells. miR-9-5p could have a role in stem cell homeostasis and cell differentiation via HES-1 gene.

Dataset Information

Harnessing isomerization-mediated manipulation of nonspecific cell/matrix interactions to reversibly trigger and suspend stem cell differentiation.

Publications

Harnessing isomerization-mediated manipulation of nonspecific cell/matrix interactions to reversibly trigger and suspend stem cell differentiation.

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