BackgroundStem cells for cardiac repair have shown promise in preclinical trials, but lower than expected retention, viability, and efficacy. Encapsulation is one potential strategy to increase viable cell retention while facilitating paracrine effects.Methods and ResultsHuman mesenchymal stem cells (hMSC) were encapsulated in alginate and attached to the heart with a hydrogel patch in a rat myocardial infarction (MI) model. Cells were tracked using bioluminescence (BLI) and cardiac function measured by transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR). Microvasculature was quantified using von Willebrand factor staining and scar measured by Masson's Trichrome. Post‐MI ejection fraction by CMR was greatly improved in encapsulated hMSC‐treated animals (MI: 34±3%, MI+Gel: 35±3%, MI+Gel+hMSC: 39±2%, MI+Gel+encapsulated hMSC: 56±1%; n=4 per group; P<0.01). Data represent mean±SEM. By TTE, encapsulated hMSC‐treated animals had improved fractional shortening. Longitudinal BLI showed greatest hMSC retention when the cells were encapsulated (P<0.05). Scar size at 28 days was significantly reduced in encapsulated hMSC‐treated animals (MI: 12±1%, n=8; MI+Gel: 14±2%, n=7; MI+Gel+hMSC: 14±1%, n=7; MI+Gel+encapsulated hMSC: 7±1%, n=6; P<0.05). There was a large increase in microvascular density in the peri‐infarct area (MI: 121±10, n=7; MI+Gel: 153±26, n=5; MI+Gel+hMSC: 198±18, n=7; MI+Gel+encapsulated hMSC: 828±56 vessels/mm2, n=6; P<0.01).ConclusionsAlginate encapsulation improved retention of hMSCs and facilitated paracrine effects such as increased peri‐infarct microvasculature and decreased scar. Encapsulation of MSCs improved cardiac function post‐MI and represents a new, translatable strategy for optimization of regenerative therapies for cardiovascular diseases.

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With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd 3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd 3+ and a 10 11 -fold greater selectivity for Gd 3+ over Zn 2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r 1 /r 2 : 66.8 mmol −1 ·s −1 / 89.2 mmol −1 ·s −1 per particle). Using T 1 -and T 2 -weighted, as well as T 2 /T 1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10-20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery.MRI | uveal melanoma | metastasis | contrast agents | T 2 /T 1 ratio imaging T umor metastasis is the main cause of nearly all human cancerrelated deaths. Liver is a common site for metastases of a variety of cancers, including melanoma, breast, pancreatic, and colon cancers (1, 2). For example, uveal melanoma, the most common primary intraocular tumor, has a 40% risk of metastasizing to the liver within 10 y of diagnosis of the primary tumor. Hepatic metastases, which occur in 95% of patients with uveal melanoma metastasis, result in death in almost all cases. This high death rate is related to the recognition of liver metastasis at a late clinical stage (at stage II or later in the TNM system) in which the metastatic uveal melanoma is resistant to currently available systemic chemotherapies (3, 4). The liver may also give rise to primary tumors such as hepatocellular carcinoma (HCC), which is the most common primary malignancy worldwide (5). However, currently there is no reliable way to detect primary liver cancer and hepatic metastases at early stages with high sensitivity and specificity.MRI is a widely used clinical imaging modality that provides exquisite soft-tissue contrast without using ionizing radiation (6, 7). More than 35% of MRI scans use MRI contrast agents, particularly paramagnetic gadolinium (Gd 3+ )-based contrast agents, which shorten T 1 and lead to an increase in MRI intensity (8). All clinically approved Gd 3+ -containing contrast agents are based on small chelators with relaxivity (r 1 and r 2 ) values around 4-6 mM −1 ·s −1 . Their low relaxivities severely limit the sensitivity of current MR imaging methods with respect to detection of lesions and treatment planning and monitoring. Repeat MRI scans are frequently requested for patients with ambiguous small lesions and are used as a routine follow-up modality for highrisk patients, but t...

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Reporter gene-based magnetic resonance imaging (MRI) offers unique insights into behavior of cells after transplantation, which could significantly benefit stem cell research and translation. Several candidate MRI reporter genes, including one that encodes for iron storage protein ferritin, have been reported, and their potential applications in embryonic stem (ES) cell research have yet to be explored. We have established transgenic mouse ES (mES) cell lines carrying human ferritin heavy chain (FTH) as a reporter gene and succeeded in monitoring the cell grafts in vivo using T 2 -weighted MRI sequences. FTH generated MRI contrast through compensatory upregulation of transferrin receptor (Tfrc) that led to increased cellular iron stored in ferritin-bound form. At a level sufficient for MRI contrast, expression of FTH posed no toxicity to mES cells and did not interfere with stem cell pluripotency as observed in neural differentiation and teratoma formation. The compatibility and functionality of ferritin as a reporter in mES cells opens up the possibility of using MRI for longitudinal noninvasive monitoring of ES cell-derived cell grafts at both molecular and cellular levels.