Transplantation of 3D MSC/HUVEC spheroids with neuroprotective and proangiogenic potentials ameliorates ischemic stroke brain injury

Hsu, Thomas T. C.; Lu, Yu-Jen; Lin, Yu‐Jie; Huang, Yu‐Ting; Hsieh, Li‐Hung; Wu, Bing-Huan; Lin, Yu‐Chun; Chen, Li-Chi; Wang, Hsin-Wen; Chuang, Jui-Che; Fang, Yi-Qiao; Huang, Chieh‐Cheng

doi:10.1016/j.biomaterials.2021.120765

Cited by 35 publications

(40 citation statements)

References 59 publications

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“…Since the in vivo therapeutic potential of RFP-and TERT-transfected MSCs has been previously verified using various animal models [5][6][7][8], we believe that these MSCs are suitable for use in the present study for further investigation. For a determination of the effect of spheroid size on therapeutic potential, a method that can fabricate spheroids with the desired diameters must be used.…”

Section: Discussionmentioning

confidence: 91%

“…For a determination of the effect of spheroid size on therapeutic potential, a method that can fabricate spheroids with the desired diameters must be used. Herein, by controlling the number of cells seeded into each well of MC hydrogel-coated plates [5][6][7][8][9], we could precisely manipulate the size of the formed spheroids, which is crucial for ensuring the consistency of the following therapeutic effect after cell transplantation. The harvested MSC spheroids contained abundant matrix components, including fibronectin, laminin, collagen, and HSPG.…”

Section: Discussionmentioning

confidence: 99%

“…Among the developed methods, we [5][6][7][8][9] and others [2,3,[10][11][12] have reported that culturing MSCs in a three-dimensional (3D) multicellular spheroid configuration can significantly enhance both the viability of administered MSCs and their overall therapeutic functions. Specifically, the spheroid configuration can more closely recapitulate the physiological 3D microenvironment than conventional two-dimensional (2D) cultures [3].…”

Section: Of 13mentioning

confidence: 99%

“…The MSC spheroids were prepared using a methylcellulose (MC) hydrogel that was not bound by cells. Twelve percent (w/v) MC solution was prepared by dissolving MC powder in phosphate buffered saline (PBS; Thermo Fisher Scientific, St. Louis, MO, USA) [5][6][7][8][9]. After autoclaving, a sterilized MC solution was employed to coat each well of a 96-well culture plate.…”

Section: Preparation Of 3d Msc Spheroidsmentioning

confidence: 99%

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

Chen

Wang

Huang

2021

Cells

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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.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Of 13mentioning

confidence: 99%

Section: Preparation Of 3d Msc Spheroidsmentioning

confidence: 99%

See 2 more Smart Citations

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

Chen

Wang

Huang

2021

Cells

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“…The culture medium was then substituted with a fresh medium with or without DNIC-2 . The migration of cells into the gap region was photographed under a microscope, and the remaining wound area was determined using ImageJ software [ 63 , 64 ].…”

Section: Methodsmentioning

confidence: 99%

Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications

Chen

Chiu

et al. 2021

IJMS

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After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of [Fe(NO)2] unit has emerged to develop biomimetic DNICs [(NO)2Fe(L)2] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 ± 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products.

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Injectable Glucose‐Releasing Microgels Enhance the Survival and Therapeutic Potential of Transplanted MSCs Under Ischemic Conditions

Huang,

Chang,

Yang

et al. 2024

Adv Healthcare Materials

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Mesenchymal stem cell (MSC)‐based therapies show potential to treat ischemic diseases owing to their versatile functions. However, sustaining MSC viability and therapeutic efficacy in ischemic tissues postengraftment remains a significant challenge. This is because, although MSCs are metabolically flexible, they fail to adapt to hypoxic conditions in the absence of glucose, leading to cell death. To overcome these issues, it is aimed to establish an injectable glucose delivery system using starch and amyloglucosidase embedded in alginate microgels. Here, starch/amyloglucosidase (S/A) microgels are engineered to continuously release glucose for seven days via enzymatic hydrolysis, thereby supporting MSC functions under ischemic conditions. In vitro tests under oxygen/glucose‐deprived conditions revealed that the S/A microgels not only maintained the viability and intracellular energy but also enhanced the pro‐angiogenic and immunomodulatory functions of MSCs. In vivo data further confirmed the pro‐survival and pro‐angiogenic effects of S/A microgels on MSCs following subcutaneous engraftment in mice. Overall, the developed S/A microgel significantly enhanced the survival and therapeutic potential of MSCs via sustained glucose delivery, highlighting its potential use in advancing MSC‐based therapies for ischemic conditions.

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Transplantation of 3D MSC/HUVEC spheroids with neuroprotective and proangiogenic potentials ameliorates ischemic stroke brain injury

Cited by 35 publications

References 59 publications

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

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

Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications

Injectable Glucose‐Releasing Microgels Enhance the Survival and Therapeutic Potential of Transplanted MSCs Under Ischemic Conditions

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