Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome

Yu, Hwan Yeul; Lee, Seungun; Ju, Hyein; Kim, Youngkyu; Shin, Ji Sun; Yun, HongDuck; Ryu, Chae‐Min; Heo, Jinbeom; Lim, Jisun; Song, Saemee; Lee, Sang-Hwa; Hong, Ki-Sung; Chung, Hyung-Min; Kim, Jun Ki; Choo, Myung‐Soo; Shin, Dong‐Myung

doi:10.1016/j.biomaterials.2021.121277

Cited by 12 publications

(12 citation statements)

References 51 publications

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“… 10 , 13 , 17-19 The MMSC treatment had superior therapeutic efficacy (both short-term and long-term) when compared to the counterparts from adult tissues such as bone marrow and umbilical cord in different rat models of bladder dysfunction and also had long-term safety in the rat model of HCl-induced IC. 10 , 13 , 16 The optimal therapeutic dosage of MMSCs in our rat model was 1 ~ 2.5 × 10 5 /mL, which was converted to HEDs. Our route of stem cell transplantation was transurethral bladder injection via cystoscopy, which is the most familiar route for most urologists.…”

Section: Discussionmentioning

confidence: 90%

“…The usage of the cryopreserved cells and lower cell dosage was different from previous preclinical studies, wherein freshly cultured cells were trypsinized, washed, and suspended in phosphate-buffered saline before injection (2 × 10 5 cells). 13 , 14 , 16 We compared the therapeutic efficacy of the SNU42-MMSCs with that of the research-grade H9-MMSCs which were used in the previous preclinical studies. 10 , 13 , 15 , 17 As a control treatment, dimethyl sulfoxide (DMSO, 67457-178-50; Mylan Pharmaceuticals Inc. Canonsburg, PA, USA) suspended in PBS was instilled for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, a combination of two-photon intravital microscopic imaging and single-cell and genome-wide transcriptome analyses demonstrated that the engrafted MMSCs were progressively integrated as perivascular cells, which could support the regenerative capacity of the damaged urothelium and stimulate the anti-inflammatory micro-environment via secreting WNT family member 5A (WNT5A). 16 Notably, hESC-derived MMSCs exhibited a superior therapeutic efficacy compared to their adult tissue-derived counterpart. Limited evidence of adverse outcomes, including abnormal growth, tumorigenesis, or immune-mediated transplant rejection over 12-month post-injection, were apparent.…”

Section: Introductionmentioning

confidence: 99%

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Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study

Shin

Ryu

et al. 2022

Stem Cells Translational Medicine

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There are still no definite treatment modalities for interstitial cystitis (IC). Meanwhile, stem cell therapy is rising as potential alternative for various chronic diseases. This study aimed to investigate the safety of the clinical-grade mesenchymal stem cells (MSCs) derived from human embryonic stem cells (hESCs), code name MR-MC-01 (SNU42-MMSCs), in IC patients. Three female IC patients with (1) symptom duration >6 months, (2) visual pain analog scale (VAS) ≥4, and (3) one or two Hunner lesions <2 cm in-office cystoscopy within 1 month were included. Under general anesthesia, participants received cystoscopic submucosal injection of SNU42-MMSCs (2.0 × 107/5 mL) at the center or margin of Hunner lesions and other parts of the bladder wall except trigone with each injection volume of 1 mL. Follow-up was 1, 3, 6, 9, and 12 months postoperatively. Patients underwent scheduled follow-ups, and symptoms were evaluated with validated questionnaires at each visit. No SNU42-MMSCs-related adverse events including immune reaction and abnormalities on laboratory tests and image examinations were reported up to 12-month follow-up. VAS pain was temporarily improved in all subjects. No de novo Hunner lesions were observed and one lesion of the first subject was not identifiable on 12-month cystoscopy. This study reports the first clinical application of transurethral hESC-derived MSC injection in three patients with IC. hESC-based therapeutics was safe and proved to have potential therapeutic efficacy in IC patients. Stem cell therapy could be a potential therapeutic option for treating IC.

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Section: Discussionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study

Shin

Ryu

et al. 2022

Stem Cells Translational Medicine

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“…Cell culture M-MSCs used in this study was provided and used by Mirae Cell Bio (Seoul, Korea). M-MSCs differentiated from H9 hESCs [30] were maintained in EGM2-MV medium (Lonza, San Diego, CA, USA) containing supplement Mix (promocell, Heidelberg, Germany) and 50 ug/ml Gentamicin (Gibco, NewYork, USA) in a humidi ed atmosphere containing 5% CO 2 at 37℃, as previously described [33]. M-MSCs at less than ten passages were used for in vitro cell culture and in vivo animal experiments.…”

Section: Induction Of Urticaria Mouse Modelmentioning

confidence: 99%

Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental urticaria by regulating the functions of mast cells and T cells

Hyun

Kang

Kim³

et al. 2023

Preprint

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Background Contact urticaria (CU) is a representative chronic inflammatory skin disease, and the symptoms progressing in stages can cause life-threatening conditions such as anaphylaxis. Mesenchymal stem cells (MSCs) are attracting attention as therapeutic agents for immune diseases. However, studies on the efficacy and mechanism of stem cell therapy for the treatment of intractable urticaria are lacking. Methods The regulatory role of administered embryonic-stem-cell-derived multipotent MSCs (M-MSCs) was evaluated on mice with CU. The functions of the M-MSCs on splenic T cells and mast cells were measured by flow cytometry analysis, histological analysis, RT-PCR, and other molecular biological approaches. The mechanism of action of the M-MSCs was examined using TGF-β neutralization in vitro and in vivo. Results The therapeutic effects of administering M-MSCs were evaluated in the developed TMA-induced urticaria model, and it was confirmed to inhibit urticarial reactions in various conditions, such as edema, itchiness, and wheal formation. In addition, M-MSC administration enabled control of the effector T cell activities in major lymphoid and peripheral tissues as well as inhibited mast-cell degranulation in the peripheral tissues. Further, the M-MSC-mediated inhibitory effects were confirmed to be dependent on TGF-β. Conclusions Our findings prove that M-MSCs promote alleviation of urticaria by controlling the activation of the inflammatory effector T cells and mast cells. We also confirm that the TGF-β mechanism is an important contributor to M-MSC-mediated inhibition of urticaria.

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“…Stem cell-based cell therapy always raises safety concerns due to its ability to form teratomas and other tumors, potential immune responses and risk of differentiation into unwanted cell types. However, M-MSCs showed no evidence of adverse events such as abnormal growth, tumor formation, or immune-mediated transplant rejection for 12 months in IC/BPS [ 10 ]. In addition, cell safety has been verified by longitudinally monitoring the biodistribution and phenotypic characteristics of M-MSCs injected through confocal microscopy and micro-endoscopy for 6 months in live animals after transplantation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation of Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Rotator Cuff Tears Model

et al. 2022

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Background: Rotator cuff tears (RCTs) induce chronic muscle weakness and shoulder pain. Treatment of RCT using surgery or drugs causes lipid infiltration and fibrosis, which hampers tissue regeneration and complete recovery. The pluripotent stem cell-derived multipotent mesenchymal stem cells (M-MSCs) represent potential candidate next-generation therapies for RCT. Methods: The difference between M-MSCs and adult-MSCs was compared and analyzed using next-generation sequencing (NGS). In addition, using a rat model of RCT, the muscle recovery ability of M-MSCs and adult-MSCs was evaluated by conducting a histological analysis and monitoring the cytokine expression level. Results: Using NGS, it was confirmed that M-MSC was suitable for transplantation because of its excellent ability to regulate inflammation that promotes tissue repair and reduced apoptosis and rejection during transplantation. In addition, while M-MSCs persisted for up to 8 weeks in vivo, they significantly reduced inflammation and adipogenesis-related cytokine levels in rat muscle. Significant differences were also confirmed in histopathological remission. Conclusions: M-MSCs remain in the body longer to modulate immune responses in RCTs and have a greater potential to improve muscle recovery by alleviating acute inflammatory responses. This indicates that M-MSCs could be used in potential next-generation RCT therapies.

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Intravital imaging and single cell transcriptomic analysis for engraftment of mesenchymal stem cells in an animal model of interstitial cystitis/bladder pain syndrome

Cited by 12 publications

References 51 publications

Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study

Safety of Human Embryonic Stem Cell-derived Mesenchymal Stem Cells for Treating Interstitial Cystitis: A Phase I Study

Embryonic-stem-cell-derived mesenchymal stem cells relieve experimental urticaria by regulating the functions of mast cells and T cells

Immunomodulation of Pluripotent Stem Cell-Derived Mesenchymal Stem Cells in Rotator Cuff Tears Model

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