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Fluorescent nanodiamonds enable quantitative tracking of human mesenchymal stem cells in miniature pigs.

ABSTRACT: Cell therapy is a promising strategy for the treatment of human diseases. While the first use of cells for therapeutic purposes can be traced to the 19th century, there has been a lack of general and reliable methods to study the biodistribution and associated pharmacokinetics of transplanted cells in various animal models for preclinical evaluation. Here, we present a new platform using albumin-conjugated fluorescent nanodiamonds (FNDs) as biocompatible and photostable labels for quantitative tracking of human placenta choriodecidual membrane-derived mesenchymal stem cells (pcMSCs) in miniature pigs by magnetic modulation. With this background-free detection technique and time-gated fluorescence imaging, we have been able to precisely determine the numbers as well as positions of the transplanted FND-labeled pcMSCs in organs and tissues of the miniature pigs after intravenous administration. The method is applicable to single-cell imaging and quantitative tracking of human stem/progenitor cells in rodents and other animal models as well.

SUBMITTER: Su LJ

PROVIDER: S-EPMC5372358 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Fluorescent nanodiamonds enable quantitative tracking of human mesenchymal stem cells in miniature pigs.

Su Long-Jyun LJ Wu Meng-Shiue MS Hui Yuen Yung YY Chang Be-Ming BM Pan Lei L Hsu Pei-Chen PC Chen Yit-Tsong YT Ho Hong-Nerng HN Huang Yen-Hua YH Ling Thai-Yen TY Hsu Hsao-Hsun HH Chang Huan-Cheng HC

Scientific reports 20170330

Cell therapy is a promising strategy for the treatment of human diseases. While the first use of cells for therapeutic purposes can be traced to the 19th century, there has been a lack of general and reliable methods to study the biodistribution and associated pharmacokinetics of transplanted cells in various animal models for preclinical evaluation. Here, we present a new platform using albumin-conjugated fluorescent nanodiamonds (FNDs) as biocompatible and photostable labels for quantitative t ...[more]

PMID: 28358111

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Project description:Clinically available materials, including allogeneic irradiated costal cartilage and fibrin glue polymer, were used as scaffolds for in vivo chondrogenic differentiation of human adipose-derived stem/stromal cells (hASCs) in the attempt to develop a more efficient treatment over current methods. Current studies include the use of growth-factor stimulation, tissue engineering, and biocompatible materials; however, most methods involve complicated processes and pose clinical limitations. In this report, the xenografts in the experimental group composed of a diced decellularized cartilage extracellular matrix (ECM), hASCs, and fibrin glue polymer were implanted into the subcutaneous layer of nude mice, and the results were compared with two groups of controls; one control group received implantation of decellularized cartilage ECM and fibrin glue polymer, and the other control group received implantation of hASCs mixed with fibrin glue polymer. To evaluate whether hASCs had in vivo chondrogenesis in the xenografts, hASCs were labeled with fluorescent nanodiamonds (FNDs), a biocompatible and photostable nanomaterial, to allow for long-term detection and histological analysis. Increased cellularity, glycosaminoglycan, and collagen deposition were found by the histological examination in the experimental group compared with control groups. With the background-free detection technique and time-gated fluorescence imaging, the numbers and locations of the FND-labeled hASCs could be detected by confocal microscopy. The chondrocyte-specific markers, such as aggrecan and type II collagen, were colocalized with cells containing signals of FNDs which indicated in vivo chondrogenesis of hASCs. Taken together, functional in vivo chondrogenesis of the hASCs could be achieved by clinically available decellularized cartilage ECM and fibrin glue polymer in the nude mice model without in vitro chondrogenic induction. The fluorescent signals of FNDs in hASCs can be detected in histological analysis, such as hematoxylin and eosin staining (H&E staining) without the interference of the autofluorescence. Our study may warrant future clinical applications of the combination of decellular cartilage ECM, fibrin glue polymer, and hASCs for cartilage repair.

Project description:UnlabelledEvidence suggests that transplanted mesenchymal stem cells (MSCs) can aid recovery of damaged myocardium caused by myocardial infarction. One possible mechanism for MSC-mediated recovery is reprogramming after cell fusion between transplanted MSCs and recipient cardiac cells. We used a Cre/LoxP-based luciferase reporter system coupled to biophotonic imaging to detect fusion of transplanted human pluripotent stem cell-derived MSCs to cells of organs of living mice. Human MSCs, with transient expression of a viral fusogen, were delivered to the murine heart via a collagen patch. At 2 days and 1 week later, living mice were probed for bioluminescence indicative of cell fusion. Cell fusion was detected at the site of delivery (heart) and in distal tissues (i.e., stomach, small intestine, liver). Fusion was confirmed at the cellular scale via fluorescence in situ hybridization for human-specific and mouse-specific centromeres. Human cells in organs distal to the heart were typically located near the vasculature, suggesting MSCs and perhaps MSC fusion products have the ability to migrate via the circulatory system to distal organs and engraft with local cells. The present study reveals previously unknown migratory patterns of delivered human MSCs and associated fusion products in the healthy murine heart. The study also sets the stage for follow-on studies to determine the functional effects of cell fusion in a model of myocardial damage or disease.SignificanceMesenchymal stem cells (MSCs) are transplanted to the heart, cartilage, and other tissues to recover lost function or at least limit overactive immune responses. Analysis of tissues after MSC transplantation shows evidence of fusion between MSCs and the cells of the recipient. To date, the biologic implications of cell fusion remain unclear. A newly developed in vivo tracking system was used to identify MSC fusion products in living mice. The migratory patterns of fusion products were determined both in the target organ (i.e., the heart) and in distal organs. This study shows, for the first time, evidence of fusion products at sites distal from the target organ and data to suggest that migration occurs via the vasculature. These results will inform and improve future, MSC-based therapeutics.

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Fluorescent nanodiamonds enable quantitative tracking of human mesenchymal stem cells in miniature pigs.

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Fluorescent nanodiamonds enable quantitative tracking of human mesenchymal stem cells in miniature pigs.

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