scholarly journals Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration

2017 ◽  
Author(s):  
Lauren Scarfe ◽  
Arthur Taylor ◽  
Jack Sharkey ◽  
Rachel Harwood ◽  
Michael Barrow ◽  
...  
Keyword(s):  
Cell Types ◽  
Arterial System ◽  
Imaging Modalities ◽  
Organ Distribution ◽  
Human Umbilical Cord ◽  
Cell Therapies ◽  
Non Invasive ◽  
Longitudinal Imaging ◽  
In Vivo Administration

AbstractBackgroundCell-based regenerative medicine therapies are now frequently tested in clinical trials. In many conditions, cell therapies are administered systemically, but there is little understanding of their fate, and adverse events are often under-reported. Currently, it is only possible to assess safety and fate of cell therapies in preclinical studies, specifically by monitoring animals longitudinally using multimodal imaging approaches. Here, using a suite of in vivo imaging modalities to explore the fate of a range of human and murine cells, we investigate how route of administration, cell type and host immune status affect the fate of administered cells.MethodsWe applied a unique imaging toolkit combining bioluminescence, optoacoustic and magnetic resonance imaging modalities to assess the safety of different human and murine cell types by following their biodistribution and persistence in mice following administration into the venous or arterial system. Results: Longitudinal imaging analyses (i) suggested that the intra-arterial route may be more hazardous than intravenous administration for certain cell types; (ii) revealed that the potential of a mouse mesenchymal stem/stromal cell (MSC) line to form tumours, depended on administration route and mouse strain; and (iii) indicated that clinically tested human umbilical cord (hUC)-derived MSCs can transiently and unexpectedly proliferate when administered intravenously to mice.ConclusionsIn order to perform an adequate safety assessment of potential cell-based therapies, a thorough understanding of cell biodistribution and fate post administration is required. The non-invasive imaging toolbox used here can expose not only the general organ distribution of these therapies, but also a detailed view of their presence within different organs and, importantly, tumourigenic potential. Our observation that the hUC-MSCs but not the human bone marrow (hBM)-derived MSCs persisted for a period in some animals, suggests that therapies with these cells should proceed with caution.

scholarly journals In Vivo Imaging of Biodegradable Implants and Related Tissue Biomarkers

Polymers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 2348
Author(s):  
Leon Riehakainen ◽  
Chiara Cavallini ◽  
Paolo Armanetti ◽  
Daniele Panetta ◽  
Davide Caramella ◽  
...  
Keyword(s):  
Imaging Modality ◽  
Imaging Techniques ◽  
Special Focus ◽  
Tissue Remodelling ◽  
Biodegradable Implant ◽  
Advantages And Disadvantages ◽  
Non Invasive ◽  
Positron Emission ◽  
Longitudinal Imaging

Non-invasive longitudinal imaging of osseointegration of bone implants is essential to ensure a comprehensive, physical and biochemical understanding of the processes related to a successful implant integration and its long-term clinical outcome. This study critically reviews the present imaging techniques that may play a role to assess the initial stability, bone quality and quantity, associated tissue remodelling dependent on implanted material, implantation site (surrounding tissues and placement depth), and biomarkers that may be targeted. An updated list of biodegradable implant materials that have been reported in the literature, from metal, polymer and ceramic categories, is provided with reference to the use of specific imaging modalities (computed tomography, positron emission tomography, ultrasound, photoacoustic and magnetic resonance imaging) suitable for longitudinal and non-invasive imaging in humans. The advantages and disadvantages of the single imaging modality are discussed with a special focus on preclinical imaging for biodegradable implant research. Indeed, the investigation of a new implant commonly requires histological examination, which is invasive and does not allow longitudinal studies, thus requiring a large number of animals for preclinical testing. For this reason, an update of the multimodal and multi-parametric imaging capabilities will be here presented with a specific focus on modern biomaterial research.

Human umbilical cord blood-derived cells differentiate into hepatocyte-like cells in the Fas-mediated liver injury model

2005 ◽  
Vol 289 (6) ◽  
pp. G1091-G1099 ◽  
Author(s):  
Kazunobu Nonome ◽  
Xiao-Kang Li ◽  
Terumi Takahara ◽  
Yusuke Kitazawa ◽  
Naoko Funeshima ◽  
...  
Keyword(s):  
Liver Injury ◽  
Umbilical Cord Blood ◽  
Fas Ligand ◽  
In Vitro Study ◽  
Cell Types ◽  
Human Umbilical Cord Blood ◽  
Specific Gene ◽  
Human Umbilical Cord

Human umbilical cord blood (HUCB) contains stem/progenitor cells, which can differentiate into a variety of cell types. In this study, we investigated whether HUCB cells differentiate into hepatocytes in vitro and in vivo. We also examined whether CD34 could be the selection marker of stem cells for hepatocytes. HUCB cells were obtained from normal full-term deliveries, and CD34+/−cells were further separated. For in vitro study, HUCB cells were cultured for 4 wk, and expressions of liver-specific genes were examined. For the in vivo study, nonobese diabetic/severe combined immunodeficient mice were subjected to liver injury by a Fas ligand-carried adenoviral vector or only radiated. Mice were treated simultaneously with or without cell transplantation of HUCB, CD34+, or CD34−cells. After 4 wk, human-specific gene/protein expression was examined. In the in vitro study, human liver-specific genes were positive after 7 days of culture. The immunofluorescent study showed positive staining of α-fetoprotein, cytokeratin 19, and albumin in round-shaped cells. In the in vivo study, immunohistochemical analysis showed human albumin-positive, hepatocyte-specific antigen-positive cells in mouse livers of the Fas ligand/transplantation group. Fluorescence in situ hybridization analysis using the human Y chromosome also showed positive signals. However, no difference between transplanted cell types was detected. In contrast, immunopositive cells were not detected in the irradiated/transplantation group. The RT-PCR result also showed human hepatocyte-specific gene expressions only in the Fas ligand/transplantation group. HUCB cells differentiated into hepatocyte-like cells in the mouse liver, and liver injury was essential during this process. The differences between CD34+and CD34−cells were not observed in human hepatocyte-specific expression.

scholarly journals Multiplexed Non-invasive in vivo Imaging to Assess Metabolism and Receptor Engagement in Tumor Xenografts

2019 ◽  
Author(s):  
Alena Rudkouskaya ◽  
Nattawut Sinsuebphon ◽  
Marien Ochoa ◽  
Joe E. Mazurkiewicz ◽  
Xavier Intes ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Metabolic Response ◽  
Imaging Modalities ◽  
Wide Field ◽  
Receptor Ligand ◽  
Non Invasive ◽  
Intracellular Drug Delivery

AbstractFollowing an ever-increased focus on personalized medicine, there is a continuing need to develop preclinical molecular imaging modalities to guide the development and optimization of targeted therapies. To date, non-invasive quantitative imaging modalities that can comprehensively assess simultaneous cellular drug delivery efficacy and therapeutic response are lacking. In this regard, Near-Infrared (NIR) Macroscopic Fluorescence Lifetime Förster Resonance Energy Transfer (MFLI-FRET) imaging offers a unique method to robustly quantify receptor-ligand engagement in vivo and subsequent intracellular internalization, which is critical to assess the delivery efficacy of targeted therapeutics. However, implementation of multiplexing optical imaging with FRET in vivo is challenging to achieve due to spectral crowding and cross-contamination. Herein, we report on a strategy that relies on a dark quencher that enables simultaneous assessment of receptor-ligand engagement and tumor metabolism in intact live mice. First, we establish that IRDye QC-1 (QC-1) is an effective NIR dark acceptor for the FRET-induced quenching of donor Alexa Fluor 700 (AF700) using in vitro NIR FLI microscopy and in vivo wide-field MFLI imaging. Second, we report on simultaneous in vivo imaging of the metabolic probe IRDye 800CW 2-deoxyglucose (2-DG) and MFLI-FRET imaging of NIR-labeled transferrin FRET pair (Tf-AF700/Tf-QC-1) uptake in tumors. Such multiplexed imaging revealed an inverse relationship between 2-DG uptake and Tf intracellular delivery, suggesting that 2-DG signal may predict the efficacy of intracellular targeted delivery. Overall, our methodology enables for the first time simultaneous non-invasive monitoring of intracellular drug delivery and metabolic response in preclinical studies.

scholarly journals Glial Cells—The Strategic Targets in Amyotrophic Lateral Sclerosis Treatment

2020 ◽  
Vol 9 (1) ◽  
pp. 261 ◽  
Author(s):  
Tereza Filipi ◽  
Zuzana Hermanova ◽  
Jana Tureckova ◽  
Ondrej Vanatko ◽  
Miroslava Anderova
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Cell Types ◽  
In Vivo Models ◽  
Cell Therapies ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease, which is characterized by the degeneration of motor neurons in the motor cortex and the spinal cord and subsequently by muscle atrophy. To date, numerous gene mutations have been linked to both sporadic and familial ALS, but the effort of many experimental groups to develop a suitable therapy has not, as of yet, proven successful. The original focus was on the degenerating motor neurons, when researchers tried to understand the pathological mechanisms that cause their slow death. However, it was soon discovered that ALS is a complicated and diverse pathology, where not only neurons, but also other cell types, play a crucial role via the so-called non-cell autonomous effect, which strongly deteriorates neuronal conditions. Subsequently, variable glia-based in vitro and in vivo models of ALS were established and used for brand-new experimental and clinical approaches. Such a shift towards glia soon bore its fruit in the form of several clinical studies, which more or less successfully tried to ward the unfavourable prognosis of ALS progression off. In this review, we aimed to summarize current knowledge regarding the involvement of each glial cell type in the progression of ALS, currently available treatments, and to provide an overview of diverse clinical trials covering pharmacological approaches, gene, and cell therapies.

scholarly journals IMMU-25. MAGNETIC PARTICLE IMAGING FOR NON-INVASIVE TRACKING OF ADOPTIVE CELL TRANSFER IN CANCER IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi124-vi124
Author(s):  
Angelie Rivera-Rodriguez ◽  
Lan Hoang-Minh ◽  
Leyda Marrero-Morales ◽  
Duane Mitchell ◽  
Carlos Rinaldi
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Cell Transfer ◽  
Cell Therapies ◽  
Non Invasive ◽  
Magnetic Particle Imaging ◽  
Particle Imaging ◽  
T Cell Transfer ◽  
Cytotoxic Function

Abstract BACKGROUND Adoptive cell therapies (ACT) are strategies being explored to boost the immune response against cancer. ACT cancer immunotherapies are effective against metastatic melanoma, leukemia, and lymphoma, but face challenges in treating other solid tumors, such as in the brain. A critical step for the success of ACT in solid cancers is achieving trafficking and persistence of T-cells at tumor sites. Glioblastoma (GBM) is the most common and aggressive cancer of the central nervous system in adults, with a prognosis of 15-18-month average patient survival after diagnosis. Biomedical imaging is often used to track cell therapies. Magnetic Particle Imaging (MPI) is a novel biomedical imaging modality enabling non-invasive visualization of the distribution of biocompatible superparamagnetic iron oxide (SPIO) tracers. OBJECTIVE Label T-cells with SPIO to non-invasively track adoptive T cell transfer immunotherapy with MPI in the context of brain cancer. METHODS Murine pmel-DsRed T-cells were isolated from the spleen of a transgenic C57BL/6 mouse, and were exposed to different SPIO concentrations ex vivo. Cell viability, phenotype, and cytotoxic function were analyzed to determine if T-cells were affected by the SPIO labeling. Moreover, in vivo experiments were performed in a murine GBM model, and labeled T-cells were injected intravenously and tracked using MPI. RESULTS The SPIO-labeling of T-cells did not affected cell viability, phenotype, or cell cytotoxic function at all tested incubation conditions. The internalized SPIO can be quantified and spatially detected using MPI both in vitro and in vivo. In addition, MPI in vivo tracking shows T-cells accumulation in liver and lungs, as well in the spleen and brain, as showed ex vivo. CONCLUSIONS SPIO-labeling of T-cells did not affected its cytotoxic function and MPI allows for in vivo tracking of adoptively T-cell transfer. MPI will provide better understanding of ACT dynamics to accelerate development of novel treatments.

scholarly journals Progenitors for the Corneal Endothelium and Trabecular Meshwork: A Potential Source for Personalized Stem Cell Therapy in Corneal Endothelial Diseases and Glaucoma

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Wing Yan Yu ◽  
Carl Sheridan ◽  
Ian Grierson ◽  
Sharon Mason ◽  
Victoria Kearns ◽  
...  
Keyword(s):  
Stem Cell ◽  
Trabecular Meshwork ◽  
Corneal Endothelium ◽  
Adult Stem Cell ◽  
Cell Types ◽  
Cell Therapies ◽  
Stem Cell Source ◽  
Embryonic Origin ◽  
Surgical Treatments

Several adult stem cell types have been found in different parts of the eye, including the corneal epithelium, conjunctiva, and retina. In addition to these, there have been accumulating evidence that some stem-like cells reside in the transition area between the peripheral corneal endothelium (CE) and the anterior nonfiltering portion of the trabecular meshwork (TM), which is known as the Schwalbe's Ring region. These stem/progenitor cells may supply new cells for the CE and TM. In fact, the CE and TM share certain similarities in terms of their embryonic origin and proliferative capacityin vivo. In this paper, we discuss the putative stem cell source which has the potential for replacement of lost and nonfunctional cells in CE diseases and glaucoma. The future development of personalized stem cell therapies for the CE and TM may reduce the requirement of corneal grafts and surgical treatments in glaucoma.

scholarly journals CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

2021 ◽  
Author(s):  
Taeyoon Kyung ◽  
Khloe S Gordon ◽  
Caleb R Perez ◽  
Patrick V Holec ◽  
Azucena Ramos ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Cell Types ◽  
Tumor Control ◽  
Antigen Receptors ◽  
Cell Therapies ◽  
Promising Tool ◽  
Signaling Domain ◽  
Screening Platform

CD19-targeted CAR therapies have successfully treated B cell leukemias and lymphomas, but many responders later relapse or experience toxicities. CAR intracellular domains (ICDs) are key to converting antigen recognition into anti-tumor effector functions. Despite the many possible immune signaling domain combinations that could be included in CARs, almost all CARs currently rely upon CD3𝛇, CD28, and/or 4-1BB signaling. To explore the signaling potential of CAR ICDs, we generated a library of 700,000 CD19 CAR molecules with diverse signaling domains and developed a high throughput screening platform to enable optimization of CAR signaling for anti-tumor functions. Our strategy identifies CARs with novel signaling domain combinations that elicit distinct T cell behaviors from a clinically available CAR, including enhanced proliferation and persistence, lower exhaustion, potent cytotoxicity in an in vitro tumor rechallenge condition, and comparable tumor control in vivo. This approach is readily adaptable to numerous disease models, cell types, and selection conditions, making it a promising tool for rapidly improving adoptive cell therapies and expanding their utility to new disease indications.

Urine Cells-derived iPSCs: An Upcoming Frontier in Regenerative Medicine

2021 ◽  
Vol 28 ◽  
Author(s):  
Sanjeev Gautam ◽  
Sangita Biswas ◽  
Birbal Singh ◽  
Ying Guo ◽  
Peng Deng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Drug Testing ◽  
Diagnostic Tools ◽  
Cell Therapies ◽  
Non Invasive ◽  
Key Issues ◽  
Induced Pluripotent

: There is a momentous surge in the development of stem cell technology as a therapeutic and diagnostic tools. Stem cell-derived cells are currently used in various clinical trials. However, key issues and challenges involve the low differentiation efficiency, integration, and functioning of transplanted stem cells-derived cells. Extraction of bone marrow, adipose, or other mesenchymal stem cells (MSCs) involves invasive methods, specialized skills, and expensive technologies. Urine-derived cells, on the other hand, are obtained by non-invasive methods. Samples can be obtained repeatedly from patients of any age. Urine-derived cells are used to generate reprogrammed or induced pluripotent stem cells (iPSCs), which can be cultured, and differentiated into various types of cell lineages for biomedical investigations and drug testing in vitro or in vivo using model animals of human diseases. Urine cell-derived iPSCs (UiPSCs) have emerged as a major area of research and immense therapeutic significance. Given that preliminary preclinical studies are successful in terms of safety and as a regenerative tool, the UiPSCs will pave the way to develop and expedite various types of autologous stem cell therapies.

Novel Evidence for the Presence of Potent, Paracrine, Pro-Angiopoietic Effects of Purified Human Umbilical Cord Blood-Derived CD133+ Cells - Implications for Adult Stem Cell Therapies in Regenerative Medicine

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4740-4740
Author(s):  
Kasia Mierzejewska ◽  
Magdalena Kucia ◽  
Janina Ratajczak ◽  
Mariusz Z Ratajczak
Keyword(s):  
Stem Cells ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Adult Stem Cell ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Cell Therapies

Abstract Abstract 4740 Background. As populations of CD34+, CD34+CXCR4+, or CD133+ cells that are enriched in stem cells, adult stem and progenitor cells purified from bone marrow (BM), mobilized peripheral blood (mPB), and umbilical cord blood (UCB) are currently employed in the clinic to treat damaged organs (e.g., heart after myocardial infarction [AMI] or injured spinal cord or liver). The cell populations expressing these phenotypes are highly enriched primarily for hematopoietic stem/progenitor cells (HSPCs) and small numbers of endothelial progenitors, and for many years it has been wrongly supposed that they can trans-dedifferentiate into tissue-specific cells. However, even when improvement of organ function is observed after employing them in therapy, the lack of a convincing demonstration for the presence of donor-recipient chimerism in treated tissues in most of the studies performed so far indicates that mechanisms other than trans-dedifferentiation of the HSPCs delivered to the damaged organs into tissue-specific cells play a significant role in some positive clinical outcomes. In support of this conclusion, evidence has accumulated that stem cells secrete a variety of growth factors, cytokines, chemokines, and bioactive lipids that interact with the surrounding microenvironment and, when used in therapy, improve cell viability in damaged organs. In particular, more attention is currently being paid to microvesicles (MVs), which are shed from the cell surface or derived from the intracellular membrane compartment as mediators in cell-to-cell communication. Hypothesis. We hypothesized that these positive outcomes in adult stem cell therapies (e.g., by employing CD133+ cells) can be explained by the paracrine effects of these cells, involving both soluble factors as well as cell membrane-derived MVs. Experimental strategies. CD133+ cells were purified from UCB by employing immunomagnetic beads (> 95% purity as checked by FACS) and incubated for 24 hours in RPMI at 37°C in a small volume of medium supplemented with 0.5% albumin. Subsequently, we harvested conditioned media (CM) from these cells and isolated CD133+ cell-shed microvesicles (MVs) by high speed centrifugation. We employed sensitive ELISA assays to measure the concentration of important pro-angiopoietic and anti-apoptotic factors in CD133+ cell-derived CM and isolated mRNA from both CD133+ cells and CD133+ cell-derived MVs for RQ-PCR analysis of gene expression. Subsequently, the chemotactic activity of CD133+ cell-derived CM and MVs was tested against human umbilical cord blood endothelial cells (HUVECs), and, in parallel, we tested whether CD133+ cell-derived CM and MVs induce major signaling pathways in HUVECs. Finally, in in vitro functional assays, we tested the ability of CD133+ cell-derived CM and MVs to induce tube formation by HUVECs and the ability of in vivo Matrigel assay implants to induce angiogenesis. Results. We observed that highly purified UCB-derived CD133+ cells express mRNAs and secrete proteins for several pro-angiopoietic factors (e.g. VEGF, KL, FGF-2, and IGF-1) into CM and shed microvesicles (MVs) from the cell surface and endosomal compartment that are enriched for mRNAs encoding VEGF, KL, FGF-2, and IGF-1. Both CD133+ cell-derived CM and MVs possessed anti-apoptotic properties, increased the in vitro cell survival of endothelial cells, stimulated phosphorylation of MAPKp42/44 and AKT in HUVECs, induced chemotactic migration, proliferation and tube formation in vitro in HUVECs, as well as stimulated in vivo angiogenesis in Matrigel implants. Conclusions. These observations suggesting an important role for CD133+ cell-derived paracrine signals should be considered when evaluating clinical outcomes using purified CD133+ cells in regenerative medicine. Overall, these cell-derived paracrine signals may explain the therapeutic benefits of adult stem cells employed in regeneration of, for example, heart AMI. Finally, we will discuss several possibilities for enhancing secretion and modulating the composition of these paracrine signals that could be explored in the clinic. Disclosures: No relevant conflicts of interest to declare.

Non-Invasive Approaches to Visualize the Endothelin Axis In Vivo Using State-of-the-Art Molecular Imaging Modalities

2009 ◽  
Vol 9 (14) ◽  
pp. 1580-1595 ◽  
Author(s):  
C. Holtke ◽  
A. Faust ◽  
H-J. Breyholz ◽  
K. Kopka ◽  
O. Schober ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
State Of The Art ◽  
Imaging Modalities ◽  
Non Invasive
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