Intranasal administration of human MSC for ischemic brain injury in the mouse: in vitro and in vivo neuroregenerative functions.
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. 1×10(6) or 2×10(6) 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 2×10(6) 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.
Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Vanessa
V
Donega
Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Cora H
CH
Nijboer
Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Luca
L
Braccioli
Cell Therapy Facility, Dept. of Clinical Pharmacy, University Medical Center Utrecht.
Ineke
I
Slaper-Cortenbach
Dept. of Symptom Research, MD Anderson Cancer Center, Houston TX, United States of America.
Annemieke
A
Kavelaars
Dept. of Neonatology, University Medical Center Utrecht.
Frank
F
van Bel
Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands; Dept. of Symptom Research, MD Anderson Cancer Center, Houston TX, United States of America.
Cobi J
CJ
Heijnen
D000281:Administration, Intranasal; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009416:Nerve Regeneration; D058953:Neural Stem Cells / Q000166:cytology; D009457:Neuroglia / Q000473:pathology; D009930:Organic Chemicals / Q000378:metabolism; D066191:Sensorimotor Cortex / Q000473:pathology
D005904:Glial Fibrillary Acidic Protein; D009930:Organic Chemicals; C070080:PKH 26