Intranasal Administration of Human MSC for Ischemic Brain Injury in the Mouse: In Vitro and In Vivo Neuroregenerative Functions

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.

Mesenchymal Stem Cells Protect Against Hypoxia-Ischemia Brain Damage by Enhancing Autophagy Through Brain Derived Neurotrophic Factor/Mammalin Target of Rapamycin Signaling Pathway

“…These findings indicate that MSCs can protect neurons from HIBD. In addition, we found that MSCs can migrate out of the lateral ventricle to other areas of the brain, which is consistent with previous study that the chemoattraction of MSCs may guide MSCs home to the ischemic lesion site . Further study showed that MSCs transplantation induced autophagosomes both in vitro and in vivo after hypoxia‐ischemia stimulation.…”

Cell tracking, survival, and differentiation capacity of adipose‐derived stem cells after engraftment in rat tissue

“…Therefore, if input signals controlling tissue homeostasis are affected in aging and chronic diseases, many factors will affect optimal survival and function of transplanted cells. In addition to their differentiation capacity, ADSCs secrete many trophic factors and immunosuppressive molecules (Donega et al, ; Wang et al, ; Whone, Kemp, Sun, Wilkins, & Scolding, ). Therefore, the therapeutic capacity and the ability of ADSCs to repair injured tissue is likely the result of both cell differentiation and paracrine alone or in combination (Kim, Park, & Sung, ; Ooi, Dheen, & Tay, ; Whone et al, ).…”

Stem cell–based therapies for the newborn lung and brain: Possibilities and challenges

“…88 . That this mechanism may involve enhancement of endogenous, tissue-resident stem cell function was suggested by in vitro studies where human BM-MSCs were shown to induce mouse neural stem cells to differentiate into neurons, leading the authors to suggest that this property represents a reflection of the neuroregenerative potential observed in vivo 98 .…”