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

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

doi:10.3390/cells10102747

Cited by 18 publications

(22 citation statements)

References 45 publications

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“…It has been shown that MSC paracrine properties can be modulated by some preconditioning methods, including the growing of MSCs under three-dimensional (3D) culture conditions. Indeed, in response to 3D MSC priming/activation, the production of factors is switched toward a more anti-inflammatory and pro-trophic phenotype that results in an improvement in MSC therapeutic properties [21,[34][35][36]. Our previous studies have shown that preconditioning of MSCs by 3D cultures enhances the secretion of functional factors.…”

Section: Introductionmentioning

confidence: 99%

Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties

Gallo

Cuscino

Contino

et al. 2022

IJMS

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Mesenchymal stromal/stem cells (MSCs) are believed to function in vivo as a homeostatic tool that shows therapeutic properties for tissue repair/regeneration. Conventionally, these cells are expanded in two-dimensional (2D) cultures, and, in that case, MSCs undergo genotypic/phenotypic changes resulting in a loss of their therapeutic capabilities. Moreover, several clinical trials using MSCs have shown controversial results with moderate/insufficient therapeutic responses. Different priming methods were tested to improve MSC effects, and three-dimensional (3D) culturing techniques were also examined. MSC spheroids display increased therapeutic properties, and, in this context, it is crucial to understand molecular changes underlying spheroid generation. To address these limitations, we performed RNA-seq on human amnion-derived MSCs (hAMSCs) cultured in both 2D and 3D conditions and examined the transcriptome changes associated with hAMSC spheroid formation. We found a large number of 3D culture-sensitive genes and identified selected genes related to 3D hAMSC therapeutic effects. In particular, we observed that these genes can regulate proliferation/differentiation, as well as immunomodulatory and angiogenic processes. We validated RNA-seq results by qRT-PCR and methylome analysis and investigation of secreted factors. Overall, our results showed that hAMSC spheroid culture represents a promising approach to cell-based therapy that could significantly impact hAMSC application in the field of regenerative medicine.

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Section: Introductionmentioning

confidence: 99%

Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties

Gallo

Cuscino

Contino

et al. 2022

IJMS

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“…Cell-based assays, including those able to mimic physiological phenomena, are important because, for instance, stem cell therapies showed promise for treating various injuries and diseases [24]. The strategies that can improve the effectiveness of drugs and nanomaterials and decrease the observed therapeutic variability are necessary for biomedical applications.…”

Section: Resultsmentioning

confidence: 99%

“…The strategies that can improve the effectiveness of drugs and nanomaterials and decrease the observed therapeutic variability are necessary for biomedical applications. Recently, scientists generated differently sized stem cell spheroids by controlling the cell number and the cultivation parameters to the estimation of matrix components value, including fibronectin, laminin, and collagen [24]. Their results revealed that expression of the mentioned molecules and immunomodulatory factors significantly altered between the different sizes of the spheroids, corresponding to the metabolic activity of the spheroids.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, traditional twodimensional cell culture approaches are still being used as a route for the risk assessment of nanomaterials and chemical agents [16][17][18][19]. While 2D cell culture platforms will remain an attractive research strategy to investigate basic cellular behaviors [20,21], these simple two dimensional in vitro cell-based assays are not suited to address more complex biological questions where cellular responses, cell-to-cell, and cell-to-matrix interactions are governed by the tissue-specific architecture [17,[22][23][24].…”

Section: Introductionmentioning

confidence: 99%

“…For instance, the surface charge and size of dendrimers exhibit as the major factors to maximize the therapeutic potential of loaded drugs by controlling their distributions to spheroid [34]. Consequently, optimization of cell migration, cell-matrix/cell interactions, NP-based cellular responses, reproducibility and scalability, compatibility with available analytical methods, dose-dependent cell viability, and interaction with nanomaterials should be addressed for 3D spheroid methods in nanotoxicology [7,16,24].…”

Section: Introductionmentioning

confidence: 99%

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Fingerprinting Metabolic Activity and Tissue Integrity of 3D Lung Cancer Spheroids under Gold Nanowire Treatment

Hashemzadeh

Kelkawi

Allahverdi

et al. 2022

Cells

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Inadequacy of most animal models for drug efficacy assessments has led to the development of improved in vitro models capable of mimicking in vivo exposure scenarios. Among others, 3D multicellular spheroid technology is considered to be one of the promising alternatives in the pharmaceutical drug discovery process. In addition to its physiological relevance, this method fulfills high-throughput and low-cost requirements for preclinical cell-based assays. Despite the increasing applications of spheroid technology in pharmaceutical screening, its application, in nanotoxicity testing is still in its infancy due to the limited penetration and uptake rates into 3D-cell assemblies. To gain a better understanding of gold nanowires (AuNWs) interactions with 3D spheroids, a comparative study of 2D monolayer cultures and 3D multicellular spheroids was conducted using two lung cancer cell lines (A549 and PC9). Cell apoptosis (live/dead assay), metabolic activity, and spheroid integrity were evaluated following exposure to AuNWs at different dose-time manners. Results revealed a distinct different cellular response between 2D and 3D cell cultures during AuNWs treatment including metabolic rates, cell viability, dose–response curves and, uptake rates. Our data also highlighted further need for more physiologically relevant tissue models to investigate in depth nanomaterial–biology interactions. It is important to note that higher concentrations of AuNWs with lower exposure times and lower concentrations of AuNWs with higher exposure times of 3 days resulted in the loss of spheroid integrity by disrupting cell–cell contacts. These findings could help to increase the understanding of AuNWs-induced toxicity on tissue levels and also contribute to the establishment of new analytical approaches for toxicological and drug screening studies.

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Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair

Chen,

Wang,

Yang

et al. 2023

Bioengineering & Transla Med

Self Cite

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The prognosis for postinjury peripheral nerve regeneration remains suboptimal. Although transplantation of exogenous Schwann cells (SCs) has been considered a promising treatment to promote nerve repair, this strategy has been hampered in practice by the limited availability of SC sources and an insufficient postengraftment cell retention rate. In this study, to address these challenges, SCs were aggregated into spheroids before being delivered to an injured rat sciatic nerve. We found that the three‐dimensional aggregation of SCs induced their acquisition of a repair phenotype, as indicated by enhanced levels of c‐Jun expression/activation and decreased expression of myelin sheath protein. Furthermore, our in vitro results demonstrated the superior potential of the SC spheroid‐derived secretome in promoting neurite outgrowth of dorsal root ganglion neurons, enhancing the proliferation and migration of endogenous SCs, and recruiting macrophages. Moreover, transplantation of SC spheroids into rats after sciatic nerve transection effectively increased the postinjury nerve structure restoration and motor functional recovery rates, demonstrating the therapeutic potential of SC spheroids. In summary, transplantation of preassembled SC spheroids may hold great potential for enhancing the cell delivery efficiency and the resultant therapeutic outcome, thereby improving SC‐based transplantation approaches for promoting peripheral nerve regeneration.

show abstract

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

Cited by 18 publications

References 45 publications

Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties

Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties

Fingerprinting Metabolic Activity and Tissue Integrity of 3D Lung Cancer Spheroids under Gold Nanowire Treatment

Schwann cells acquire a repair phenotype after assembling into spheroids and show enhanced in vivo therapeutic potential for promoting peripheral nerve repair

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