Enhancement of Subcutaneously Transplanted β Cell Survival Using 3D Stem Cell Spheroids with Proangiogenic and Prosurvival Potential

Yu, Chih‐Ping; Juang, Jyuhn‐Huarng; Lin, Yu‐Jie; Kuo, Ching‐Wen; Huang, Chieh‐Cheng

doi:10.1002/adbi.201900254

Cited by 19 publications

(38 citation statements)

References 46 publications

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“…Therapeutic cells that are delivered in a 3D spheroid configuration have been demonstrated to have a higher therapeutic potential (Huang et al, 2015;Yu et al, 2020). It has been demonstrated that cell transplantation using a multicellular 3D spheroid conformation can achieve a better therapeutic outcome than using cell suspension, as cell-cell and cell-ECM interactions are completely preserved during implantation (Chen et al, 2013;Huang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Aqueous methylcellulose (MC; 12% by w/v; Sigma-Aldrich) was prepared in phosphate buffered saline (5 g/L) solution (Huang et al, 2014;Yu et al, 2020). Fifty microliters MC solution was applied into each well of a 96-well culture plate and incubated at 37 • C for 30 min before adding 150 µL culture medium that contained 10,000 cbMSC-derived SCLCs.…”

Section: Preparation Of 3d Spheroids Of Cbmsc-derived Sclcsmentioning

confidence: 99%

“…To address the abovementioned issues, this study aims to transplant cbMSC-derived SC-like cells (SCLCs) raised using a non-genetic approach in the configuration of multicellular threedimensional (3D) spheroid, which is known to recapitulate the in vivo physiological conditions (Lee et al, 2016;Kim et al, 2019) and improve the cell retention and survival after injection (Lee et al, 2011;Huang et al, 2014). As reported by our (Yu et al, 2020) and other groups (Zhang et al, 2016;Petrenko et al, 2017), the 3D cell spheroids possess enhanced intercellular interaction and well-preserved ECM and can be harvested without the use of proteolytic enzymes, thus benefiting the cellular engraftment and the ultimate therapeutic efficacy of cell therapy. Using a rat model of sciatic nerve crush injury (Sung et al, 2012;Zhang et al, 2017), we demonstrated that intraepineurial transplantation of 3D cbMSC-derived SCLC spheroids effectively promoted peripheral nerve regeneration and hindlimb motor functional recovery.…”

Section: Introductionmentioning

confidence: 99%

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3D Spheroids of Umbilical Cord Blood MSC-Derived Schwann Cells Promote Peripheral Nerve Regeneration

Lin

Lee

Chang

et al. 2020

Front. Cell Dev. Biol.

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Schwann cells (SCs) are promising candidates for cell therapy due to their ability to promote peripheral nerve regeneration. However, SC-based therapies are hindered by the lack of a clinically renewable source of SCs. In this study, using a well-defined non-genetic approach, umbilical cord blood mesenchymal stem cells (cbMSCs), a clinically applicable cell type, were phenotypically, epigenetically, and functionally converted into SC-like cells (SCLCs) that stimulated effective sprouting of neuritic processes from neuronal cells. To further enhance their therapeutic capability, the cbMSC-derived SCLCs were assembled into three-dimensional (3D) cell spheroids by using a methylcellulose hydrogel system. The cell–cell and cell–extracellular matrix interactions were well-preserved within the formed 3D SCLC spheroids, and marked increases in neurotrophic, proangiogenic and anti-apoptotic factors were detected compared with cells that were harvested using conventional trypsin-based methods, demonstrating the superior advantage of SCLCs assembled into 3D spheroids. Transplantation of 3D SCLC spheroids into crush-injured rat sciatic nerves effectively promoted the recovery of motor function and enhanced nerve structure regeneration. In summary, by simply assembling cells into a 3D-spheroid conformation, the therapeutic potential of SCLCs derived from clinically available cbMSCs for promoting nerve regeneration was enhanced significantly. Thus, these cells hold great potential for translation to clinical applications for treating peripheral nerve injury.

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Section: Discussionmentioning

confidence: 99%

Section: Preparation Of 3d Spheroids Of Cbmsc-derived Sclcsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3D Spheroids of Umbilical Cord Blood MSC-Derived Schwann Cells Promote Peripheral Nerve Regeneration

Lin

Lee

Chang

et al. 2020

Front. Cell Dev. Biol.

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“…Currently, several approaches (hanging drop, centrifugal pellet, spinner flask, patterned surface, and magnetic or acoustic levitation of cells) and materials (non-adhesive substrates, superhydrophobic/superhydrophilic surfaces, and porous 3D scaffolds) have been developed as culture platforms for 3D microtissue fabrication (Lin and Chang, 2008;Achilli et al, 2012;Cui et al, 2017;Yu et al, 2020). Despite these being proven to be useful for generating 3D microtissues, each of these methods may have some limitations that hinder their widespread application in various biomedical domains.…”

Section: Introductionmentioning

confidence: 99%

Development of a Novel Hanging Drop Platform for Engineering Controllable 3D Microenvironments

Cho

Chiang

Hsieh

et al. 2020

Front. Cell Dev. Biol.

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Conventional biomedical research is mostly performed by utilizing a two-dimensional monolayer culture, which fails to recapitulate the three-dimensional (3D) organization and microenvironment of native tissues. To overcome this limitation, several methods are developed to fabricate microtissues with the desired 3D microenvironment. However, they tend to be time-consuming, labor-intensive, or costly, thus hindering the application of 3D microtissues as models in a wide variety of research fields. In the present study, we have developed a pressure-assisted network for droplet accumulation (PANDA) system, an easy-to-use chip that comprises a multichannel fluidic system and a hanging drop cell culture module for uniform 3D microtissue formation. This system can control the desired artificial niches for modulating the fate of the stem cells to form the different sizes of microtissue by adjusting the seeding density. Furthermore, a large number of highly consistent 3D glomerulus-like heterogeneous microtissues that are composed of kidney glomerular podocytes and mesenchymal stem cells have been formed successfully. These data suggest that the developed PANDA system can be employed as a rapid and economical platform to fabricate microtissues with tunable 3D microenvironment and cellular heterogeneity, thus can be employed as tissue-mimicking models in various biomedical research.

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“…28 As a result, we anticipated that the presence of Herein, hybrid 3D cell spheroids composed of podocytes (P), MSCs (M), and HUVECs (E) were prepared using a methylcellulose (MC) hydrogel system reported in our previous publications. 21,23,29 Spheroids with two (PM and PE) or one (P only) cell type served as controls. By exploring the mutual relationships among these cell types, we found that the maturation and engraftment of the administered podocytes were further strengthened by their interaction with the surrounding MSCs and HUVECs.…”

mentioning

confidence: 99%

Injection of hybrid 3D spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells into the renal cortex improves kidney function and replenishes glomerular podocytes

Yang

Chen

Jhuang

et al. 2021

Bioengineering & Transla Med

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Podocytes are highly differentiated epithelial cells that are crucial for maintaining the glomerular filtration barrier in the kidney. Podocyte injury followed by depletion is the major cause of pathological progression of kidney diseases. Although cell therapy has been considered a promising alternative approach to kidney transplantation for the treatment of kidney injury, the resultant therapeutic efficacy in terms of improved renal function is limited, possibly owing to significant loss of engrafted cells. Herein, hybrid three-dimensional (3D) cell spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells were designed to mimic the glomerular microenvironment and as a cell delivery vehicle to replenish the podocyte population by cell transplantation. After creating a native glomerulus-like condition, the expression of multiple genes encoding growth factors and basement membrane factors that are strongly associated with podocyte maturation and functionality was significantly enhanced. Our in vivo results demonstrated that intrarenal transplantation of podocytes in the form of hybrid 3D cell spheroids improved engraftment efficiency and replenished glomerular podocytes. Moreover, the proteinuria of the experimental mice with hypertensive nephropathy was effectively reduced. These data clearly demonstrated the potential of hybrid 3D cell spheroids for repairing injured kidneys.

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Enhancement of Subcutaneously Transplanted β Cell Survival Using 3D Stem Cell Spheroids with Proangiogenic and Prosurvival Potential

Cited by 19 publications

References 46 publications

3D Spheroids of Umbilical Cord Blood MSC-Derived Schwann Cells Promote Peripheral Nerve Regeneration

3D Spheroids of Umbilical Cord Blood MSC-Derived Schwann Cells Promote Peripheral Nerve Regeneration

Development of a Novel Hanging Drop Platform for Engineering Controllable 3D Microenvironments

Injection of hybrid 3D spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells into the renal cortex improves kidney function and replenishes glomerular podocytes

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