Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes

Yeh, Hsi-Yi; Liu, Bing-Hsien; Sieber, Martin; Hsu, Shan‐hui

doi:10.1186/1471-2164-15-10

Cited by 88 publications

(93 citation statements)

References 74 publications

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“…(CXCL1 and CXCL2) were upregulated (>2-fold, top 50 upregulated genes in the microarray data are shown in bold); whereas 6.3%, or 1,223 genes, including extracellular matrix (ECM)/its regulatory molecules (COL1A1, COL1A2, and CTGF) and actin/its regulatory molecules (ACTA2 and ACTB) were downregulated (>2-fold, top 50 downregulated genes in the microarray data are shown in bold) in MSC spheroids, consistent with previous studies [6,29]. These findings were confirmed by TaqMan-based qRT-PCR and PCR-arrays (Table 2 and Figs.…”

Section: Dramatic Change In Gene Expression Profiles In 3d Spheroidalsupporting

confidence: 76%

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Cesarz

Funnell

Guan

et al. 2016

Stem Cells and Development

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Cell therapy with adult mesenchymal stem cells (MSCs) is a promising approach to regenerative medicine and autoimmune diseases. There are various approaches to improve the efficacy of MSC-based therapeutics, and MSC preparation as spheroidal aggregates, or MSC spheroids, is a novel preparatory and delivery method. Spheroid formation induces a dramatic change in the gene expression profile of MSCs. Self-activation of interleukin-1 (IL1) signaling was shown to be upstream of both pro-and anti-inflammatory genes in MSC spheroids, but the molecular pathways that initiate IL1 signaling remain unknown. As bone morphogenic protein (BMP)2 upregulation precedes that of IL1B expression during spheroid formation, we hypothesized that BMP2 signaling triggers IL1 signaling in MSC spheroids. Contrary to expectations, BMP2 signaling decreased expression of IL1B and downstream genes in a SMAD6-dependent manner. Conversely, IL1B signaling enhanced BMP2 expression. Another major difference between two-dimensional (2D) monolayer culture and three-dimensional (3D) spheroid culture is the Young's elasticity modulus, or stiffness, of the materials surrounding the cells, as there is a million-fold difference between a plastic surface for standard 2D culture (GPa) and 3D spheroidal aggregates (0.1 kPa). We tested another hypothesis that soft elasticity-associated mechanosignaling initiates the gene expression change during spheroid formation. Results showed that both BMP2 expression and inflammatory signaling are upregulated in an elasticity-associated signaling-dependent manner in MSCs. Lastly, BMP2 signaling enhanced cell survival and cell spreading of MSC spheroids. In summary, our study suggests that soft elasticity and BMP2 signaling are critical for MSC spheroids.

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Section: Dramatic Change In Gene Expression Profiles In 3d Spheroidalsupporting

confidence: 76%

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Cesarz

Funnell

Guan

et al. 2016

Stem Cells and Development

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“…This analysis may provide further supports to the angiogenesis and will be considered in the future. On the other hand, it remains unclear if the self‐assembled MSC spheroids are superior to other MSC spheroids in vivo in spite of the different in vitro properties . This will be a further subject of study.…”

Section: Discussionmentioning

confidence: 95%

Self‐assembled adult adipose‐derived stem cell spheroids combined with biomaterials promote wound healing in a rat skin repair model

Hsu

Hsieh

2015

Wound Repair Regeneration

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Adult adipose-derived stem cells (ASCs) are a type of multipotent mesenchymal stem cells (MSCs) with easy availability and serve as a potential cell source for cell-based therapy. Three-dimensional MSC spheroids may be derived from the self-assembly of individual MSCs grown on certain polymer membranes. In this study, we demonstrated that the self-assembled ASC spheroids on chitosan-hyaluronan membranes expressed more cytokine genes (fibroblast growth factor 1, vascular endothelial growth factor, and chemokine [C-C motif] ligand 2) as well as migration-associated genes (chemokine [C-X-C motif] receptor type 4 and matrix metalloprotease 1) compared with ASC dispersed single cells grown on culture dish. To evaluate the in vivo effects of these spheroids, we applied ASC single cells and ASC spheroids in a designed rat skin repair model. Wounds of 15 × 15 mm were created on rat dorsal skin, where ASCs were administered and covered with hyaluronan gel/chitosan sponge to maintain a moist environment. Results showed that skin wounds treated with ASC spheroids had faster wound closure and a significantly higher ratio of angiogenesis. Tracking of fluorescently labeled ASCs showed close localization of ASC spheroids to microvessels, suggesting enhanced angiogenesis through paracrine effects. Based on the in vitro and in vivo results, the self-assembled ASC spheroids may be a promising cellular source for skin tissue engineering and wound regeneration.

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“…The self‐assembly process of stem cells on chitosan substrates was different from that occurred in hanging drop, suspension culture, or observed on non‐adherent surfaces or micropatterned substrates. The expression of calcium signaling‐associated genes participating in the process of spheroid formation on chitosan was higher than that on non‐adherent surfaces . Besides, many genes associated with the multilineage differentiation capacities and those associated with the anti‐inflammatory properties of MSCs were also up‐regulated.…”

Section: Spheroids Formed By Culture Substrates Versus Other Methodsmentioning

confidence: 95%

Biomaterial Substrate‐Mediated Multicellular Spheroid Formation and Their Applications in Tissue Engineering

Tseng

Wong

Hsieh

et al. 2017

Biotechnology Journal

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Three-dimentional (3D) multicellular aggregates (spheroids), compared to the traditional 2D monolayer cultured cells, are physiologically more similar to the cells in vivo. So far there are various techniques to generate 3D spheroids. Spheroids obtained from different methods have already been applied to regenerative medicine or cancer research. Among the cell spheroids created by different methods, the substrate-derived spheroids and their forming mechanism are unique. This review focuses on the formation of biomaterial substrate-mediated multicellular spheroids and their applications in tissue engineering and tumor models. First, the authors will describe the special chitosan substrate-derived mesenchymal stem cell (MSC) spheroids and their greater regenerative capacities in various tissues. Second, the authors will describe tumor spheroids derived on chitosan and hyaluronan substrates, which serve as a simple in vitro platform to study 3D tumor models or to perform cancer drug screening. Finally, the authors will mention the self-assembly process for substrate-derived multiple cell spheroids (co-spheroids), which may recapitulate the heterotypic cell-cell interaction for co-cultured cells or crosstalk between different types of cells. These unique multicellular mono-spheroids or co-spheroids represent a category of 3D cell culture with advantages of biomimetic cell-cell interaction, better functionalities, and imaging possibilities.

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Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes

Cited by 88 publications

References 74 publications

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Soft Elasticity-Associated Signaling and Bone Morphogenic Protein 2 Are Key Regulators of Mesenchymal Stem Cell Spheroidal Aggregates

Self‐assembled adult adipose‐derived stem cell spheroids combined with biomaterials promote wound healing in a rat skin repair model

Biomaterial Substrate‐Mediated Multicellular Spheroid Formation and Their Applications in Tissue Engineering

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