Biodistribution of intranasally administered human mesenchymal stem cells in a preclinical model of encephalopathy of prematurity

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Prematurely born babies are susceptible to developing encephalopathy of prematurity (EoP), causing long-term neurodevelopmental impairments. Mesenchymal stem cells (MSCs) show promising potential for treating neurological diseases, including EoP. Intranasal (I.N.) delivery of MSCs is a non-invasive route of administration and has been shown to support neuroregeneration in preclinical models. However, there is a limited understanding of the biodistribution and fate of MSCs post-administration. This knowledge is essential for optimizing the therapeutic efficacy of MSC-based therapies and their clinical translation. Therefore, we assessed the biodistribution and fate of human Wharton’s jelly-derived MSCs (hMSCs) post-I.N. delivery in a rat model of EoP. To achieve this, male and female rat (RccHan: WIST) pups were exposed to a double-hit model consisting of fetal inflammation and postnatal hypoxia (FIPH), followed by the I.N. administration of hMSCs at 6 days post-hypoxia. Fluorescent gold mesoporous silica-coated nanoparticles (AuMS) were used to label hMSCs, to quantify the biodistribution of hMSCs in the brain and systemic off-target organs using inductively coupled plasma mass spectrometry, and to assess the fate of hMSCs in tissue sections using their fluorescent properties. Here, we provide a proof of principle that I.N. hMSC treatment restores myelin deficits in rats exposed to FIPH. The distribution patterns of AuMS-labeled hMSC-based material show a relatively large loss of signal immediately after I.N. delivery via the gastrointestinal tract. At 24 h post-I.N. administration, the remaining AuMS-labeled hMSC-based material migrates throughout the brain with a notable number of hMSCs in the cerebrospinal fluid. Remarkably, the percentage of hMSC-based material migrating to the rostral cerebrum is significantly increased in FIPH compared to control animals. Moreover, the distribution pattern of AuMS signal is diffuse throughout the cerebrum, and half of the MSCs are colocalizing with microglia/macrophages at 24 h post-administration. In conclusion, we demonstrate for the first time an in-depth (semi-)quantitative biodistribution analysis of hMSC-based material after I.N. administration in a rat model of EoP. This study provides critical insights into hMSC biodistribution after I.N. administration, which is essential information to bridge the gap between hMSCs’ preclinical successes and their clinical translation. Moreover, it demonstrates that brain regeneration can be achieved even when only a minimal number of hMSCs reach the brain.

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