A dual-enzymatically cross-linked injectable gelatin hydrogel loaded with BMSC improves neurological function recovery of traumatic brain injury in rats

Yao, M.; Gao, Feng; Xu, Rongbin; Zhang, Junni; Chen, Yi-Hao; Guan, Fangxia

doi:10.1039/c9bm00749k

Cited by 56 publications

(29 citation statements)

References 39 publications

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“…An increasing number of studies have demonstrated MSC-derived exosomes (MSC-exos) have innate therapeutic potential by virtue of their intrinsic cargoes. MSCexos have shown excellent efficacy in tissue repair and regeneration of many organs, including liver, lung, cartilage, myocardium, brain, spinal cord, and kidney [15][16][17][18][19][20][21][22]. Taking acute kidney injury (AKI) as an example, MSC-exos exert a series of renoprotective and regenerative effects through various mechanisms, including anti-inflammatory, immunomodulatory, anti-necroptosis, anti-apoptosis, and promoting cell proliferation [15,23].…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury

et al. 2020

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Background: Exosomes derived from mesenchymal stem cells (MSC-exos) have been demonstrated with great potential in the treatment of multiple human diseases including acute kidney injury (AKI) by virtue of their intrinsic cargoes. However, there are major challenges of low yield and the lack of an established biomanufacturing platform to efficiently produce MSC-exos, thereby limiting their therapeutic application. Here, we aimed to establish a novel strategy to produce MSC-exos with a hollow fiber bioreactor-based three-dimensional (3D) culture system and evaluate the therapeutic efficacy of 3D-exosomes (3D-exos) on AKI. Methods: Mesenchymal stem cells (MSCs) were isolated from fresh human umbilical cord and cultured in twodimensional (2D) flasks. 2 × 10 8 MSCs were inoculated into the hollow fiber bioreactor for 3D culture. The culture supernatants were collected every 1 or 2 days for isolating exosomes. Exosomes from 2D (2D-exos) and 3D cultures were characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting analysis of exosome markers. The yield of exosomes from 2 × 10 8 MSCs seeded in 2D and 3D culture system was compared, based on protein quantification. The therapeutic efficacy of 2D-exos and 3D-exos was investigated in a murine model of cisplatin-induced AKI in vivo and in vitro. Results: 3D culture did not significantly change the surface markers of MSCs, as well as the morphology, size, and exosomal markers of 3D-exos when compared to those of 2D-exos. Compared with conventional 2D culture, the 3D culture system increased total exosome production up to 19.4-fold. 3D-exos were more concentrated in the harvested supernatants (15.5-fold) than 2D-exos, which led to a higher exosome collection efficiency of 3D culture system. In vivo, both 2D-exos and 3D-exos significantly alleviated cisplatin-induced murine AKI evidenced by improved renal function, attenuated pathological changes of renal tubules, reduced inflammatory factors, and repressed T cell and macrophage infiltration. Impressively, 3D-exos were more effective than 2D-exos. Moreover, 3D-exos were taken up by tubular epithelial cells (TECs) with improved efficiency, thereby exhibiting superior antiinflammatory effect and improved viability of TECs in vitro.

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Section: Introductionmentioning

confidence: 99%

Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury

et al. 2020

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“…The grafting of phenol groups onto gelatin was analyzed by the 1 H NMR and UV‐vis spectra of gelatin and GH polymer (Figure S1a, b). The results clearly presented that the integration value corresponding to phenol groups (6.7–7.1 ppm and 275 nm) of GH was much higher than that of gelatin, confirming the successful conjugation of HPA to the gelatin backbones (Lee et al, 2014; Yao et al, 2019c). Additionally, the phenolic contents of these gelatin derivatives reached 23.27 μmol in 1 g of GH determined by the standard curve of HPA (Figure S1c).…”

Section: Resultsmentioning

confidence: 63%

Control the fate of human umbilical cord mesenchymal stem cells with dual‐enzymatically cross‐linked gelatin hydrogels for potential applications in nerve regeneration

Gao

et al. 2020

J Tissue Eng Regen Med

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Stem‐cell‐based therapy is a promising strategy to treat challenging neurological diseases, while its application is hindered primarily by the low viability and uncontrolled differentiation of stem cell. Hydrogel can be properly engineered to share similar characteristics with the target tissue, thus promoting cell viability and directing cell differentiation. In this study, we proposed a new dual‐enzymatically cross‐linked and injectable gelatin hydrogel for regulating survival, proliferation, and differentiation of human umbilical cord mesenchymal stem cells (hUC‐MSCs) in a three‐dimensional matrix. This injectable gelatin hydrogel was formed by oxidative coupling of gelatin–hydroxyphenyl acid conjugates catalyzed by hydrogen horseradish peroxidase (HRP) and choline oxidase (ChOx). Modulus and H2O2 release can be well controlled by ChOx activity. Results from calcein‐AM/PI staining and Ki67 immunofluorescence tests demonstrated that the survival and proliferation behavior of hUC‐MSCs were highly enhanced in HRP1UChOx0.25U hydrogel with lower modulus and less H2O2 release compared with other groups. Attractively, the expression of neuron‐specific markers β‐III tubulin, neurofilament light chain (NFL), and synapsin‐1 was significantly increased in HRP1UChOx0.25U hydrogel as well. Additionally, in vitro hemolysis test and in vivo HE staining data highlighted the good biocompatibility. Undoubtedly, this injectable gelatin hydrogel's ability to control hUC‐MSCs' fate holds enormous potentials in nervous disorders' therapy and nerve regeneration.

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“…Injectable hydrogels are highly suitable for the treatment of TBI [ 1 , 14 , 15 ], since its injection can minimize the damage to the skull and ensure the direct access of its-carried medicine to the lesion [ 16 ]. In addition, hydrogels can be carriers for various bioactive elements, such as stem cells, cytokines and drugs.…”

Section: Introductionmentioning

confidence: 99%

Neuro-regenerative imidazole-functionalized GelMA hydrogel loaded with hAMSC and SDF-1α promote stem cell differentiation and repair focal brain injury

Zheng

Chen

et al. 2021

Bioactive Materials

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Brain tissues that are severely damaged by traumatic brain injury (TBI) is hardly regenerated, which leads to a cavity or a repair with glial scarring. Stem-cell therapy is one viable option to treat TBI-caused brain tissue damage, whose use is, whereas, limited by the low survival rate and differentiation efficiency of stem cells. To approach this problem, we developed an injectable hydrogel using imidazole groups-modified gelatin methacrylate (GelMA-imid). In addition, polydopamine (PDA) nanoparticles were used as carrier for stromal-cell derived factor-1 (SDF-1α). GelMA-imid hydrogel loaded with PDA@SDF-1α nanoparticles and human amniotic mesenchymal stromal cells (hAMSCs) were injected into the damaged area in an in-vivo cryogenic injury model in rats. The hydrogel had low module and its average pore size was 204.61 ± 41.41 nm, which were suitable for the migration, proliferation and differentiation of stem cells. In-vitro cell scratch and differentiation assays showed that the imidazole groups and SDF-1α could promote the migration of hAMSCs to injury site and their differentiation into nerve cells. The highest amount of nissl body was detected in the group of GelMA-imid/SDF-1α/hAMSCs hydrogel in the in-vivo model. Additionally, histological analysis showed that GelMA-imid/SDF-1α/hAMSCs hydrogel could facilitate the regeneration of regenerate endogenous nerve cells. In summary, the GelMA-imid/SDF-1α/hAMSCs hydrogel promoted homing and differentiation of hAMSCs into nerve cells, and showed great application potential for the physiological recovery of TBI.

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A dual-enzymatically cross-linked injectable gelatin hydrogel loaded with BMSC improves neurological function recovery of traumatic brain injury in rats

Abstract: BMSC-laden gelatin hydrogels dual-enzymatically cross-linked by GOX and HRP could significantly promote the neurological function recovery of TBI in rats.

Cited by 56 publications

References 39 publications

Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury

Three-dimensional culture of MSCs produces exosomes with improved yield and enhanced therapeutic efficacy for cisplatin-induced acute kidney injury

Control the fate of human umbilical cord mesenchymal stem cells with dual‐enzymatically cross‐linked gelatin hydrogels for potential applications in nerve regeneration

Neuro-regenerative imidazole-functionalized GelMA hydrogel loaded with hAMSC and SDF-1α promote stem cell differentiation and repair focal brain injury

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