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

Abstract

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.

Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis

“…On the other hand, upregulation of inflammatory mediators in the damaged nerve can limit the efficacy of cell‐based therapy 21 . The overexpression of inflammatory cytokines not only can decrease the native regeneration of tissue, 21 but also can also cause apoptosis of grafted cells 34 . The majority of grafted MSCs may not survive the first few days posttransplantation 22 .…”

“…The samples were homogenized in 1 g/mL homogenate buffer and centrifuged at 10 000 rpm for 10 minutes at 4°C. Supernatants were collected for the measurement of BDNF, GDNF, IL‐6, and TNF‐α with an ELISA kit (Boster, Wuhan, China), according to the manufacturer's instructions 34 . All samples were analyzed in triplicate.…”

Smart diagnostic nano-agents for cerebral ischemia

“…In recent work, transplanted green fluorescent protein (GFP)-expressing MSCs pre-incubated with SPIONs-loaded polymersomes were used to analyze migration, long-term fate, and survival of MSCs. 40 Interestingly, although treatment with MSCs was accompanied by a reduction of the infarct region and by an improved functional outcome, most transplanted GFP-MSCs did not survive at 8 weeks after grafting (number of grafted cells sharply decreased at 2 weeks after transplant). Moreover, only a small percentage of the survived cells differentiated into astrocytes, but not into neurons.…”

Peritumoral administration of IFNβ upregulated mesenchymal stem cells inhibits tumor growth in an orthotopic, immunocompetent rat glioma model

“…The hypointense signal intensity and its volume on T2*W images of animals in each group at each time point were measured to evaluate the homing, engraftment, distribution and survival of transplanted IFNβ-FTH-MSCs, as previously described. 14 The relative signal intensity of the grafted cells was calculated as follows: relative signal intensity=(SI NB −SI GC )/SI NB ×100%, where SI GC represents the signal intensity of the grafted cells and SI NB represents the signal intensity of the contralateral normal brain parenchyma. The tumor volume of animals in each group at each time point was measured on T2W images to assess the therapeutic effect, as previously described.…”