Abstract
Intranasal treatment with C57BL/6 MSCs reduces lesion volume and improves motor and cognitive behavior in the neonatal hypoxic-ischemic (HI) mouse model. In this study, we investigated the potential of human MSCs (hMSCs) to treat HI brain injury in the neonatal mouse. Assessing the regenerative capacity of hMSCs is crucial for translation of our knowledge to the clinic. We determined the neuroregenerative potential of hMSCs in vitro and in vivo by intranasal administration 10 d post-HI in neonatal mice. HI was induced in P9 mouse pups. 1×106 or 2×106 hMSCs were administered intranasally 10 d post-HI. Motor behavior and lesion volume were measured 28 d post-HI. The in vitro capacity of hMSCs to induce differentiation of mouse neural stem cell (mNSC) was determined using a transwell co-culture differentiation assay. To determine which chemotactic factors may play a role in mediating migration of MSCs to the lesion, we performed a PCR array on 84 chemotactic factors 10 days following sham-operation, and at 10 and 17 days post-HI. Our results show that 2×106 hMSCs decrease lesion volume, improve motor behavior, and reduce scar formation and microglia activity. Moreover, we demonstrate that the differentiation assay reflects the neuroregenerative potential of hMSCs in vivo, as hMSCs induce mNSCs to differentiate into neurons in vitro. We also provide evidence that the chemotactic factor CXCL10 may play an important role in hMSC migration to the lesion site. This is suggested by our finding that CXCL10 is significantly upregulated at 10 days following HI, but not at 17 days after HI, a time when MSCs no longer reach the lesion when given intranasally. The results described in this work also tempt us to contemplate hMSCs not only as a potential treatment option for neonatal encephalopathy, but also for a plethora of degenerative and traumatic injuries of the nervous system.
Highlights
Neonatal encephalopathy due to perinatal hypoxia-ischemia (HI) is an important cause of mortality and long-term neurological deficits such as cerebral palsy, seizures and mental retardation in babies born at term [1,2,3,4,5]
Human mesenchymal stem/stromal cells (MSCs) induce mouse NSCs to differentiate in vitro As the success of the in vivo experiment depends on the capacity of hMSCs to interact with the mouse host environment despite differences in species, we tested whether human MSCs were functional with respect to being capable of inducing expression of bIII-Tubulin by murine NSCs. bIII-Tubulin is a microtubule protein that is almost exclusively expressed by immature neurons [28]
Our results show that the number of nestin+ cells, as a marker for undifferentiated stem cells, increased after co-culture with hMSCs (Fig. 2A and E; Table S2)
Summary
Neonatal encephalopathy due to perinatal hypoxia-ischemia (HI) is an important cause of mortality and long-term neurological deficits such as cerebral palsy, seizures and mental retardation in babies born at term [1,2,3,4,5]. Therapeutic strategies for neonatal encephalopathy remain scarce. Developing new treatment options for the newborn infant that effectively prevent or diminish the development of encephalopathy is of pivotal importance. MSCs are valuable as a therapeutic tool as they are hardly immunogenic due to a lack of MHC class II expression and costimulatory proteins (e.g. CD80, CD86 and CD40) [8,9]. Several clinical trials are currently investigating the efficacy and safety of MSCs as a treatment option for various pathologies [10]
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