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Comparative strategies for stem cell biodistribution in a preclinical study.

ABSTRACT: Stem cell therapy represents the potential alternative effective strategy for some diseases that lack effective treatment currently. Correspondingly, it is crucial to establish high-sensitive and reliable quantification assay for tracing exogenous cell migration. In the present study, we first used both bioluminescence imaging (BLI) indirect labeling (human norepinephrine transporter-luciferase reporter system) and ⁸⁹zirconium (⁸⁹Zr)-hNSCs direct labeling combined with positron emission tomography/computer tomography (PET/CT) system for tracking human neural stem cells (hNSCs) migration into the brain via nasal administration in preclinical study. But the above two methods failed to give the biodistribution profile due to their low sensitivity. Considering its superior sensitivity and absolute quantitation capability, we developed and validated the droplet digital PCR (ddPCR) targeting species-specific gene in frozen and paraffin sections, slices, and whole blood with the sensitivity of 100-200 hNSCs. Accurate and high throughput quantification could be performed using ddPCR with the coefficient of variation (CVs) of lower quality control (LQC) below 30%. In combination with immunohistochemistry and ddPCR, we confirmed the migration of hNSCs into the brain via nasal administration, which supported the efficacy of hNSCs in MPTP-treated mice, an animal model of Parkinson's disease. In conclusion, the present study is the first to report the application of ddPCR in the pharmacokinetics profile description of tracking of hNSCs in preclinical studies.

SUBMITTER: Wang F

PROVIDER: S-EPMC7470780 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Comparative strategies for stem cell biodistribution in a preclinical study.

Wang Fang F Wang Zhe Z Wang Fen F Dong Kelly K Zhang Jing J Sun Yun-Juan YJ Liu Chun-Feng CF Xing Mei-Jie MJ Cheng Xue X Wei Su S Zheng Jia-Wei JW Zhao Xiong-Fei XF Wang Xiao-Ming XM Fu Jie J Song Hai-Feng HF

Acta pharmacologica Sinica 20191108 4

Stem cell therapy represents the potential alternative effective strategy for some diseases that lack effective treatment currently. Correspondingly, it is crucial to establish high-sensitive and reliable quantification assay for tracing exogenous cell migration. In the present study, we first used both bioluminescence imaging (BLI) indirect labeling (human norepinephrine transporter-luciferase reporter system) and <sup>89</sup>zirconium (<sup>89</sup>Zr)-hNSCs direct labeling combined with posi ...[more]

PMID: 31705124

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Project description:Mesenchymal stem/stromal cell (MSC) therapy is a promising approach for treatment of as yet incurable detrusor underactivity (DUA), which is characterized by decreased detrusor contraction strength and/or duration, leading to prolonged bladder emptying. In the present study, we demonstrated the therapeutic potential of human embryonic stem cell (ESC)-derived multipotent MSCs (M-MSCs) in a diabetic rat model of DUA. Diabetes mellitus (DM) was induced by intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) into 8-week-old female Sprague-Dawley rats. Three weeks later, various doses of M-MSCs (0.25, 0.5, and 1 × 106 cells) or an equivalent volume of PBS were injected into the outer layer of the bladder. Awake cystometry, organ bath, histological, and gene expression analyses were evaluated 1 week (short-term) or 2 and 4 weeks (long-term) after M-MSC transplantation. STZ-induced diabetic rats developed DUA, including phenotypes with significantly longer micturition intervals, increased residual urine amounts and bladder capacity, decreased micturition pressure on awake cystometry, and contractile responses to various stimuli in organ bath studies. Muscle degeneration, mast cell infiltration, fibrosis, and apoptosis were present in the bladders of DM animals. A single local transplantation of M-MSCs ameliorated DUA bladder pathology, including functional changes and histological evaluation, and caused few adverse outcomes. Immunostaining and gene expression analysis revealed that the transplanted M-MSCs supported myogenic restoration primarily by engrafting into bladder tissue via pericytes, and subsequently exerting paracrine effects to prevent apoptotic cell death in bladder tissue. The therapeutic efficacy of M-MSCs was superior to that of human umbilical cord-derived MSCs at the early time point (1 week). However, the difference in efficacy between M-MSCs and human umbilical cord-derived MSCs was statistically insignificant at the later time points (2 and 4 weeks). Collectively, the present study provides the first evidence for improved therapeutic efficacy of a human ESC derivative in a preclinical model of DM-associated DUA.

Project description:Background: The efficacy of mesenchymal stem cells (MSCs) in treating liver fibrosis has been supported by various clinical studies. However, stem cell transplantation is limited in clinical application due to its low survival rate, low liver implantation rate, and possible carcinogenicity. Recently, there has been increasing interest in the use of MSC-exos due to their widespread availability, low immunogenicity, and non-carcinogenic properties. Numerous studies have demonstrated the potential of MSC-exos in treating liver fibrosis and preventing progression to end-stage liver disease. Objective: This study aimed to systematically investigate the efficacy of MSC-exos single administration in the treatment of hepatic fibrosis and the combined advantages of MSC-exos in combination with drug therapy (MSC-exos-drugs). Methods: Data sources included PubMed, Web of Science, Embase, and the Cochrane Library, which were built up to January 2024. The population, intervention, comparison, outcomes, and study design (PICOS) principle was used to screen the literature, and the quality of the literature was evaluated to assess the risk of bias. Finally, the data from each study's outcome indicators were extracted for a combined analysis. Results: After screening, a total of 18 papers (19 studies) were included, of which 12 involved MSC-exos single administration for the treatment of liver fibrosis and 6 involved MSC-exos-drugs for the treatment of liver fibrosis. Pooled analysis revealed that MSC-exos significantly improved liver function, promoted the repair of damaged liver tissue, and slowed the progression of hepatic fibrosis and that MSC-exos-drugs were more efficacious than MSC-exos single administration. Subgroup analyses revealed that the use of AD-MSC-exos resulted in more consistent and significant efficacy when MSC-exos was used to treat hepatic fibrosis. For MSC-exos-drugs, a more stable end result is obtained by kit extraction. Similarly, infusion through the abdominal cavity is more effective. Conclusion: The results suggest that MSC-exos can effectively treat liver fibrosis and that MSC-exos-drugs are more effective than MSC-exos single administration. Although the results of the subgroup analyses provide recommendations for clinical treatment, a large number of high-quality experimental validations are still needed. Systematic Review Registration: CRD42024516199.

Project description:BackgroundThe therapeutic effects of human embryonic stem cell-derived multipotent mesenchymal stem cells (M-MSCs) were evaluated for detrusor underactivity (DUA) in a rat model with atherosclerosis-induced chronic bladder ischemia (CBI) and associated mechanisms.MethodsSixteen-week-old male Sprague-Dawley rats were divided into five groups (n = 10). The DUA groups underwent 30 bilateral repetitions of endothelial injury to the iliac arteries to induce CBI, while the sham control group underwent a sham operation. All rats used in this study received a 1.25% cholesterol diet for 8 weeks. M-MSCs at a density of 2.5, 5.0, or 10.0 × 105 cells (250 K, 500 K, or 1000 K; K = a thousand) were injected directly into the bladder 7 weeks post-injury, while the sham and DUA group were treated only with vehicle (phosphate buffer solution). One week after M-MSC injection, awake cystometry was performed on the rats. Then, the bladders were harvested, studied in an organ bath, and prepared for histological and gene expression analyses.ResultsCBI by iliac artery injury reproduced voiding defects characteristic of DUA with decreased micturition pressure, increased micturition interval, and a larger residual volume. The pathological DUA properties were improved by M-MSC treatment in a dose-dependent manner, with the 1000 K group producing the best efficacy. Histological analysis revealed that M-MSC therapy reduced CBI-induced injuries including bladder fibrosis, muscular loss, and apoptosis. Transplanted M-MSCs mainly engrafted as vimentin and NG2 positive pericytes rather than myocytes, leading to increased angiogenesis in the CBI bladder. Transcriptomes of the CBI-injured bladders were characterized by the complement system, inflammatory, and ion transport-related pathways, which were restored by M-MSC therapy.ConclusionsSingle injection of M-MSCs directly into the bladder of a CBI-induced DUA rat model improved voiding profiles and repaired the bladder muscle atrophy in a dose-dependent manner.

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Comparative strategies for stem cell biodistribution in a preclinical study.

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Comparative strategies for stem cell biodistribution in a preclinical study.

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