Jiaji Mao

A novel polymeric micelle used for in vivo MR imaging tracking of neural stem cells in acute ischemic stroke

Transplantation of neural stem cells (NSCs) is a promising treatment strategy for acute ischemic stroke. In vivo tracking of the therapeutic stem cells in the host brain after transplantation is essential not only to ensure the safety and efficacy of the treatment, but also to better understand their migrational dynamics and regeneration potential. Many polymeric nanoparticles have been developed to label stem cells for in vivo tracking by magnetic resonance imaging (MRI), optical imaging (OI) or other imaging modalities. However, the non-degradability and presence of cellular toxicity of the nanoparticles restrict their clinical applications. In this study, we developed a novel cationic polymeric micelles based on amphipathic polymer of biodegradable hydrophilic poly(aspartic acid-dimethylethanediamine) (PAsp(DMA)) that were conjugated with two molecules of hydrophobic cholic acid (CA) by lysine. Image labels, superparamagnetic iron oxide nanoparticles (SPIONs) and fluorescent nile red were simultaneously loaded into the micelles to label NSCs. The labeling capacity, efficiency and cytotoxicity of the cationic micelles were determined. The in vivo MRI tracking of the therapeutic NSCs in acute ischemic stroke was also explored. Our results showed that this type of cationic polymeric micelles achieved a high efficient and safe labeling of NSCs and resulted in reliable in vivo MRI tracking of therapeutic stem cells in acute ischemic stroke, but without detrimental effect. The cationic, biodegradable polymeric micelles are highly translatable for clinical application and can be used as a versatile nanoplatform for stem cell labeling and subsequently in vivo tracking in regenerative medicine.

Superparamagnetic Iron Oxide Nanoparticles-Complexed Cationic Amylose for In Vivo Magnetic Resonance Imaging Tracking of Transplanted Stem Cells in Stroke

Cell-based therapy with mesenchymal stem cells (MSCs) is a promising strategy for acute ischemic stroke. In vivo tracking of therapeutic stem cells with magnetic resonance imaging (MRI) is imperative for better understanding cellular survival and migrational dynamics over time. In this study, we develop a novel biocompatible nanocomplex (ASP-SPIONs) based on cationic amylose, by introducing spermine and the image label, ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs), to label MSCs. The capacity, efficiency, and cytotoxicity of the nanocomplex in transferring SPIONs into green fluorescence protein-modified MSCs were tested; and the performance of in vivo MRI tracking of the transplanted cells in acute ischemic stroke was determined. The results demonstrated that the new class of SPIONs-complexed nanoparticles based on biodegradable amylose can serve as a highly effective and safe carrier to transfer magnetic label into stem cells. A reliable tracking of transplanted stem cells in stroke was achieved by MRI up to 6 weeks, with the desirable therapeutic benefit of stem cells on stroke retained. With the advantages of a relatively low SPIONs concentration and a short labeling period, the biocompatible complex of cationic amylose with SPIONs is highly translatable for clinical application. It holds great promise in efficient, rapid, and safe labeling of stem cells for subsequent cellular MRI tracking in regenerative medicine.

In Vivo Targeted MR Imaging of Endogenous Neural Stem Cells in Ischemic Stroke

Acute ischemic stroke remains a leading cause of death and disability. Endogenous neurogenesis enhanced via activation of neural stem cells (NSCs) could be a promising method for stroke treatment. In vivo targeted tracking is highly desirable for monitoring the dynamics of endogenous NSCs in stroke. Previously, we have successfully realized in vivo targeted MR imaging of endogenous NSCs in normal adult mice brains by using anti-CD15 antibody-conjugated superparamagnetic iron oxide nanoparticles (anti-CD15-SPIONs) as the molecular probe. Herein, we explore the performance of this molecular probe in targeted in vivo tracking of activated endogenous NSCs in ischemic stroke. Our study showed that intraventricular injection of anti-CD15-SPIONs could label activated endogenous NSCs in situ seven days after ischemic stroke, which were detected as enlarged areas of hypo-intense signals on MR imaging at 7.0 T. The treatment of cytosine arabinosine could inhibit the activation of endogenous NSCs, which was featured by the disappearance of areas of hypo-intense signals on MR imaging. Using anti-CD15-SPIONs as imaging probes, the dynamic process of activation of endogenous NSCs could be readily monitored by in vivo MR imaging. This targeted imaging strategy would be of great benefit to develop a new therapeutic strategy utilizing endogenous NSCs for ischemic stroke.

In Vivo Long-Term Tracking of Neural Stem Cells Transplanted into an Acute Ischemic Stroke model with Reporter Gene-Based Bimodal MR and Optical Imaging

Transplantation of neural stem cells (NSCs) is emerging as a new therapeutic approach for stroke. Real-time imaging of transplanted NSCs is essential for successful cell delivery, safety monitoring, tracking cell fate and function, and understanding the interactions of transplanted cells with the host environment. Magnetic resonance imaging (MRI) of magnetic nanoparticle-labeled cells has been the most widely used means to track stem cells in vivo. Nevertheless, it does not allow for the reliable discrimination between live and dead cells. Reporter gene-based MRI was considered as an alternative strategy to overcome this shortcoming. In this work, a class of lentiviral vector-encoding ferritin heavy chain (FTH) and enhanced green fluorescent protein (EGFP) was constructed to deliver reporter genes into NSCs. After these transgenic NSCs were transplanted into the contralateral hemisphere of rats with acute ischemic stroke, MRI and fluorescence imaging (FLI) were performed in vivo for tracking the fate of transplanted cells over a long period of 6 wk. The results demonstrated that the FTH and EGFP can be effectively and safely delivered to NSCs via the designed lentiviral vector. The distribution and migration of grafted stem cells could be monitored by bimodal MRI and FLI. FTH can be used as a robust MRI reporter for reliable reporting of the short-term viability of cell grafts, whereas its capacity for tracking the long-term viability of stem cells remains dependent on several confounding factors such as cell death and the concomitant reactive inflammation.

Value of severe liver iron overload for assessing heart iron levels in thalassemia major patients

The relationship between severe liver iron overload (LIO) and heart iron overload (HIO) in transfusion‐dependent patients with thalassemia major (TM) is uncertain. Whether severe LIO can serve as an index for assessing heart iron deposition has vital clinical significance. Therefore, our aim is to determine if a close relationship exists between severe LIO and HIO.

In vivo tracking of the tropism of mesenchymal stem cells to malignant gliomas using reporter gene‐based MR imaging

Mesenchymal stem cells (MSCs) have emerged as a promising cellular vehicle for gene therapy of malignant gliomas due to their property of tumor tropism. However, MSCs may show bidirectional and divergent effects on tumor growth. Therefore, a robust surveillance system with a capacity for noninvasive monitoring of the homing, distribution and fate of stem cells in vivo is highly desired for developing stem cell‐based gene therapies for tumors. In this study, we used ferritin gene‐based magnetic resonance imaging (MRI) to track the tumor tropism of MSCs in a rat orthotopic xenograft model of malignant glioma. MSCs were transduced with lentiviral vectors expressing ferritin heavy chain (FTH) and enhanced green fluorescent protein (eGFP). Intra‐arterial, intravenous and intertumoral injections of these FTH transgenic MSCs (FTH‐MSCs) were performed in rats bearing intracranial orthotopic C6 gliomas. The FTH‐MSCs were detected as hypointense signals on T2‐ and T2*‐weighted images on a 3.0 T clinical MRI. After intra‐arterial injection, 17% of FTH‐MSCs migrated toward the tumor and gradually diffused throughout the orthotopic glioma. This dynamic process could be tracked in vivo by MRI up to 10 days of follow‐up, as confirmed by histology. Moreover, the tumor tropism of MSCs showed no appreciable impact on the progression of the tumor. These results suggest that FTH reporter gene‐based MRI can be used to reliably track the tropism and fate of MSCs after their systemic transplantation in orthotopic gliomas. This real‐time in vivo tracking system will facilitate the future development of stem cell‐based therapies for malignant gliomas.

Intravoxel incoherent motion MRI in differentiation between recurrent carcinoma and postchemoradiation fibrosis of the skull base in patients with nasopharyngeal carcinoma.

To determine the capacity of intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in differential diagnosis between recurrent carcinoma and postchemoradiation fibrosis of skull base in patients with nasopharyngeal carcinoma (NPC).

Axillary Sentinel Lymph Nodes in Breast Cancer: Quantitative Evaluation at Dual-Energy CT

Purpose To evaluate the diagnostic performance of quantitative parameters derived from dual-energy CT for the preoperative diagnosis of metastatic sentinel lymph nodes (SLNs) in participants with breast cancer. Materials and Methods For this prospective study, dual-phase contrast agent-enhanced CT was performed in female participants with breast cancer from June 2015 to December 2017. Quantitative dual-energy CT parameters and morphologic parameters were compared between metastatic and nonmetastatic SLNs. The quantitative parameters were fitted to univariable and multivariable logistic regression models. The diagnostic role of morphologic and quantitative parameters was analyzed by receiver operating characteristic curves and compared by using the McNemar test. Results This study included 193 female participants (mean age, 47.6 years ± 10.1; age range, 22-79 years). Quantitative dual-energy CT parameters including slope of the spectral Hounsfield unit curve (λHu) measured at both arterial and venous phases, normalized iodine concentration at both arterial and venous phase, and normalized effective atomic number at the venous phase were higher in metastatic than in nonmetastatic SLNs (P value range, ≤.001 to .031). Univariable and multivariable logistic regression analyses showed that venous phase λHu (in Hounsfield units per kiloelectron-volt) was the best single parameter for the detection of metastatic SLNs. The accuracy of the venous phase λHu for detecting metastatic SLNs was 90.5% on a per-lymph node basis and 87.0% on a per-patient basis. The accuracy and specificity at venous phase λHu was higher than their counterparts in the morphologic parameters (P < .001). Conclusion Dual-energy CT is a complementary means for the preoperative identification of sentinel lymph nodes metastases in participants with breast cancer.

Cationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation

Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here we show that ~40 nm cationic nanoparticles (cNP) can scavenge cfDNA derived from RA patients and inhibit the activation of primary synovial fluid monocytes and fibroblast-like synoviocytes. Using clinical scoring, micro-CT images, MRI, and histology, we show that intravenous injection of cNP into a CpG-induced mouse model or collagen-induced arthritis rat model can relieve RA symptoms including ankle and tissue swelling, and bone and cartilage damage. This culminates in the manifestation of partial mobility recovery of the treated rats in a rotational cage test. Mechanistic studies on intracellular trafficking and biodistribution of cNP, as well as measurement of cytokine expression in the joints and cfDNA levels in systemic circulation and inflamed joints also correlate with therapeutic outcomes. This work suggests a new direction of nanomedicine in treating inflammatory diseases.Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here the authors use ~40 nm cationic nanoparticles to scavenge cfDNA, and demonstrate the potential for nanomedicine to relieve debilitating RA symptoms.

The long-term fate of mesenchymal stem cells labeled with magnetic resonance imaging-visible polymersomes in cerebral ischemia

Understanding the long-term fate and potential mechanisms of mesenchymal stem cells (MSCs) after transplantation is essential for improving functional benefits of stem cell-based stroke treatment. Magnetic resonance imaging (MRI) is considered an attractive and clinically translatable tool for longitudinal tracking of stem cells, but certain controversies have arisen in this regard. In this study, we used SPION-loaded cationic polymersomes to label green fluorescent protein (GFP)-expressing MSCs to determine whether MRI can accurately reflect survival, long-term fate, and potential mechanisms of MSCs in ischemic stroke therapy. Our results showed that MSCs could improve the functional outcome and reduce the infarct volume of stroke in the brain. In vivo MRI can verify the biodistribution and migration of grafted cells when pre-labeled with SPION-loaded polymersome. The dynamic change of low signal volume on MRI can reflect the tendency of cell survival and apoptosis, but may overestimate long-term survival owing to the presence of iron-laden macrophages around cell graft. Only a small fraction of grafted cells survived up to 8 weeks after transplantation. A minority of these surviving cells were differentiated into astrocytes, but not into neurons. MSCs might exert their therapeutic effect via secreting paracrine factors rather than directing cell replacement through differentiation into neuronal and/or glial phenotypes.