Abstract
Noninvasive cell tracking in vivo has the potential to advance stem cell-based therapies into the clinic. Magnetic resonance imaging (MRI) provides an excellent image-guidance platform; however, existing MR cell labeling agents are fraught with limited specificity. To address this unmet need, we developed a highly efficient manganese porphyrin contrast agent, MnEtP, using a two-step synthesis. In vitro MRI at 3 Tesla on human embryonic stem cells (hESCs) demonstrated high labeling efficiency at a very low dose of 10 µM MnEtP, resulting in a four-fold lower T 1 relaxation time. This extraordinarily low dose is ideal for labeling large cell numbers required for large animals and humans. Cell viability and differentiation capacity were unaffected. Cellular manganese quantification corroborated MRI findings, and the agent localized primarily on the cell membrane. In vivo MRI of transplanted hESCs in a rat demonstrated excellent sensitivity and specificity of MnEtP for noninvasive stem cell tracking.
Highlights
Cell transplantation therapy based on human embryonic stem cells has great potential in treating complex medical conditions such as cardiovascular disease, autoimmune disease, cancer, and neurological disorders [1, 2] as they are pluripotent and have unlimited proliferation potential [3, 4]
Manganese insertion was accomplished with 85% yield. e structure was confirmed by high resolution mass spectrometry (MS), and the purity was confirmed to be >95% by Mn flame atomic absorption spectroscopy and HPLC
Due to the hydrophobic nature of MnEtP, stock solutions of the agent were prepared in dimethyl sulfoxide (DMSO) and infused into the media for cell labeling
Summary
Cell transplantation therapy based on human embryonic stem cells (hESCs) has great potential in treating complex medical conditions such as cardiovascular disease, autoimmune disease, cancer, and neurological disorders [1, 2] as they are pluripotent and have unlimited proliferation potential [3, 4]. E ability to noninvasively visualize the therapeutic cells in vivo would help verify their initial distribution, their continued survival, engraftment, and correlation with improved organ function. Cellular MRI has most commonly been performed with superparamagnetic iron oxides (SPIOs) for its high sensitivity [5]. This darkcontrast approach su ers from obliteration of signal in surrounding anatomy and nonspeci city in regard to the source of dark signal, be they microbleeds, air/tissue interface, or released SPIO internalized by macrophages [7, 8]
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