Endosome-triggered ion-releasing nanoparticles as therapeutics to enhance the angiogenic efficacy of human mesenchymal stem cells

Im, Gwang Bum; Jung, Euiyoung; Kim, Yeong Hwan; Kim, Yu Jin; Kim, Sung Won; Jeong, Gajin; Lee, Tae Jin; Kim, Dong Ik; Kim, Jinheung; Hyeon, Taeghwan; Yu, Taekyung; Bhang, Suk Ho

doi:10.1016/j.jconrel.2020.05.038

Cited by 19 publications

(14 citation statements)

References 67 publications

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“…The cellular and molecular connections might also have been related to iron metabolism. 13,51 Overall, the aforementioned findings indicate that the prepared Mn-and Fe-containing hydrogels had potent stimulatory effects on the migration of fibroblast cells to the scratched area.…”

Section: ■ Results and Discussionmentioning

confidence: 76%

“…Moreover, it was shown that the intracellular delivery of Fe ions might lead to beneficial biological effects such as gene expression and cell migration. The cellular and molecular connections might also have been related to iron metabolism. , Overall, the aforementioned findings indicate that the prepared Mn- and Fe-containing hydrogels had potent stimulatory effects on the migration of fibroblast cells to the scratched area.…”

Section: Resultsmentioning

confidence: 91%

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Injectable Antibacterial Gelatin-Based Hydrogel Incorporated with Two-Dimensional Nanosheets for Multimodal Healing of Bacteria-Infected Wounds

Kalantari-Hesari

Haghi

Alinezhad³

et al. 2022

ACS Appl. Bio Mater.

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The design and development of multifunctional injectable hydrogels with high photothermal antibacterial activity and shape adaptability to accelerate bacteria-infected wound healing is of critical importance in clinical applications. In this study, a hybrid hydrogel composed of gelatin, iron, and MnO 2 nanosheets was prepared by multiple interactions, including coordinative and hydrogen bonding as well as electrostatic attraction. The introduced MnO 2 and Fe components made the hydrogels photothermally and chemodynamically active, thereby endowing them with potent antibacterial capabilities against both Gram-negative and Grampositive bacteria. Because of the Fenton activity of the hydrogels, they could produce abandoned oxygen, which is highly crucial in the healing process of wounds. They also showed good cytocompatibility and hemocompatibility as well as high hemostatic properties. Moreover, the injectable hydrogels could fill irregular wounds and significantly accelerate bacteria-infected wound healing through decreasing the inflammatory response and increasing blood vessels. These features indicated the promising potential of the multifunctional hydrogel for healing infected full-thickness wounds.

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Section: ■ Results and Discussionmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 91%

Injectable Antibacterial Gelatin-Based Hydrogel Incorporated with Two-Dimensional Nanosheets for Multimodal Healing of Bacteria-Infected Wounds

Kalantari-Hesari

Haghi

Alinezhad³

et al. 2022

ACS Appl. Bio Mater.

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“…The increment of HIF-1α gene expression in hADSCs might be related to the intracellular reactive oxygen species (ROS) level [ 39 ]. Previously iron ions have been reported to have interaction with mitochondrial membrane and upregulate ROS generation [ 40 ]. Since the ROS is known to upregulate HIF-1α gene expression, representative HIF-1α -downstream angiogenic factor such as VEGF might have been also upregulated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells

Kim

Jung

et al. 2020

Nano Convergence

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Cell therapy based on human adipose derived stem cells (hADSCs) is a known potential therapeutic approach to induce angiogenesis in ischemic diseases. However, the therapeutic efficacy of direct hADSC injection is limited by a low cell viability and poor cell engraftment after administration. To improve the outcomes of this kind of approach, various types of nanoparticles have been utilized to improve the therapeutic efficacy of hADSC transplantation. Despite their advantages, the adverse effects of nanoparticles, such as genetic damage and potential oncogenesis based on non-degradable property of nanoparticles prohibit the application of nanoparticles toward the clinical applications. Herein, we designed a transition metal based inorganic nanocluster able of pH-selective degradation (ps-TNC), with the aim of enhancing an hADSC based treatment of mouse hindlimb ischemia. Our ps-TNC was designed to undergo degradation at low pH conditions, thus releasing metal ions only after endocytosis, in the endosome. To eliminate the limitations of both conventional hADSC injection and non-degradable property of nanoparticles, we have collected conditioned medium (CM) from the ps-TNC treated hADSCs and administrated it to the ischemic lesions. We found that intracellular increment of transition metal ion upregulated the hypoxia-inducible factor 1α, which can induce vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expressions. Based on the molecular mechanism, the secretion of VEGF and bFGF by ps-TNC treated hADSCs showed a significant improvement compared to that of untreated cells. Injecting the CM collected from ps-TNC treated hADSCs into the mouse hindlimb ischemia model (ps-TNC-CM group) showed significantly improved angiogenesis in the lesions, with improved limb salvage and decreased muscle degeneration compared to the group injected with CM collected from normal hADSCs (CM group). This study suggests a novel strategy, combining a known angiogenesis molecular mechanism with both an improvement on conventional stem cell therapy and the circumvention of some limitations still present in modern approaches based on nanoparticles.

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“…Iron-ion-induced ROS also upregulates hypoxia inducible factor-1α (HIF-1α) expression in MSCs, which in turn, can elevate MSC secretion of paracrine factors like VEGF (supports angiogenesis during wound repair) and basic fibroblast growth factor (bFGF) (supports angiogenesis) [ 59 ]. Essentially, HIF-1α acts as a transcription factor, binds to VEGF promoter and induces VEGF expression [ 56 , 60 , 61 ].…”

Section: Msc Tropism Towards Tumour/inflammation and Contextual Ionp-induced Msc Alterationsmentioning

confidence: 99%

Iron Oxide Nanoparticles in Mesenchymal Stem Cell Detection and Therapy

Mehta

2022

Stem Cell Rev and Rep

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Mesenchymal stem cells (MSCs) exhibit regenerative and reparative properties. However, most MSC-related studies remain to be translated for regular clinical usage, partly due to challenges in pre-transplantation cell labelling and post-transplantation cell tracking. Amidst this, there are growing concerns over the toxicity of commonly used gadolinium-based contrast agents that mediate in-vivo cell detection via MRI. This urges to search for equally effective but less toxic alternatives that would facilitate and enhance MSC detection post-administration and provide therapeutic benefits in-vivo. MSCs labelled with iron oxide nanoparticles (IONPs) have shown promising results in-vitro and in-vivo. Thus, it would be useful to revisit these studies before inventing new labelling approaches. Aiming to inform regenerative medicine and augment clinical applications of IONP-labelled MSCs, this review collates and critically evaluates the utility of IONPs in enhancing MSC detection and therapeutics. It explains the rationale, principle, and advantages of labelling MSCs with IONPs, and describes IONP-induced intracellular alterations and consequent cellular manifestations. By exemplifying clinical pathologies, it examines contextual in-vitro, animal, and clinical studies that used IONP-labelled bone marrow-, umbilical cord-, adipose tissue- and dental pulp-derived MSCs. It compiles and discusses studies involving MSC-labelling of IONPs in combinations with carbohydrates (Venofer, ferumoxytol, dextran, glucosamine), non-carbohydrate polymers [poly(L-lysine), poly(lactide-co-glycolide), poly(L-lactide), polydopamine], elements (ruthenium, selenium, gold, zinc), compounds/stains (silica, polyethylene glycol, fluorophore, rhodamine B, DAPI, Prussian blue), DNA, Fibroblast growth Factor-2 and the drug doxorubicin. Furthermore, IONP-labelling of MSC exosomes is reviewed. Also, limitations of IONP-labelling are addressed and methods of tackling those challenges are suggested. Graphical Abstract

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Endosome-triggered ion-releasing nanoparticles as therapeutics to enhance the angiogenic efficacy of human mesenchymal stem cells

Cited by 19 publications

References 67 publications

Injectable Antibacterial Gelatin-Based Hydrogel Incorporated with Two-Dimensional Nanosheets for Multimodal Healing of Bacteria-Infected Wounds

Injectable Antibacterial Gelatin-Based Hydrogel Incorporated with Two-Dimensional Nanosheets for Multimodal Healing of Bacteria-Infected Wounds

Regulation of intracellular transition metal ion level with a pH-sensitive inorganic nanocluster to improve therapeutic angiogenesis by enriching conditioned medium retrieved from human adipose derived stem cells

Iron Oxide Nanoparticles in Mesenchymal Stem Cell Detection and Therapy

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