Modulation of Inherent Niches in 3D Multicellular MSC Spheroids Reconfigures Metabolism and Enhances Therapeutic Potential.

Li-Chi Chen,Hsin-Wen Wang,Chieh-Cheng Huang

doi:10.3390/cells10102747

Abstract

Multicellular spheroids show three-dimensional (3D) organization with extensive cell–cell and cell–extracellular matrix interactions. Owing to their native tissue-mimicking characteristics, mesenchymal stem cell (MSC) spheroids are considered promising as implantable therapeutics for stem cell therapy. Herein, we aim to further enhance their therapeutic potential by tuning the cultivation parameters and thus the inherent niche of 3D MSC spheroids. Significantly increased expression of multiple pro-regenerative paracrine signaling molecules and immunomodulatory factors by MSCs was observed after optimizing the conditions for spheroid culture. Moreover, these alterations in cellular behaviors may be associated with not only the hypoxic niche developed in the spheroid core but also with the metabolic reconfiguration of MSCs. The present study provides efficient methods for manipulating the therapeutic capacity of 3D MSC spheroids, thus laying solid foundations for future development and clinical application of spheroid-based MSC therapy for regenerative medicine.

Highlights

IntroductionMesenchymal stem cells (MSCs) have been widely explored for their broad-ranging potential in regenerative medicine, especially in cell therapy [1]
Michael Raghunath and Anna BlockiMesenchymal stem cells (MSCs) have been widely explored for their broad-ranging potential in regenerative medicine, especially in cell therapy [1]
mesenchymal stem cell (MSC) that were derived from human umbilical cord blood and transfected with human telomerase reverse transcriptase (TERT) and red fluorescence protein (RFP) using nonviral vectors were acquired from the Bioresource Collection and Research Center, Food

Summary

Introduction

Mesenchymal stem cells (MSCs) have been widely explored for their broad-ranging potential in regenerative medicine, especially in cell therapy [1]. Accumulating evidence indicates that it is the secretome of MSCs exhibit the major and diverse therapeutic functions, including anti-apoptosis, pro-angiogenesis, and immunomodulatory effects [1]. By secreting a broad spectrum of bioactive molecules in free forms or encapsulated in extracellular vesicles, the administered MSCs can establish a pro-regenerative microenvironment to promote tissue repair. Since the behavior and functionality of MSCs are tightly regulated by their surrounding niche, several cell priming/preconditioning approaches, including supplementation with bioactive molecules or chemicals, manipulation of oxygen tension, and employment of various culture conditions/substrates, have been proposed to improve the therapeutic efficiency of MSC transplantation [4]

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