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Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling.
Stem Cell Res Ther 2018; 9(1):326SC

Abstract

BACKGROUND

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have been shown to prevent brain damage and improve neurocognition following intraventricular hemorrhage (IVH). However, the molecular mechanisms underlying the effects of hUCB-MSCs are still elusive. Thus, as the hippocampus is essential for learning, memory, and cognitive functions and is intimately involved in the ventricular system, making it a potential site of IVH-induced injury, we determined the molecular basis of the effects of hUCB-derived MSCs on hippocampal neurogenesis and the recovery of hippocampal neural circuits after IVH in a rodent model.

METHODS

We inflicted severe IVH injury on postnatal day 4 (P4) in rats. After confirmation of successful induction of IVH using MRI (P5), intracerebroventricular administration of MSCs (ICV-MSC) was performed at 2 days post-injury (P6). For hippocampal synaptic determination, a rat entorhinal-hippocampus (EH) organotypic slice co-culture (OSC) was performed using day 3 post-IVH brains (P7) with or without ICV-MSCs. A similar strategy of experiments was applied to those rats receiving hUCB-MSC transfected with BDNF-Si-RNA for knockdown of BDNF or scrambled siRNA controls after IVH. The molecular mechanism of the MSCs effects on neurogenesis and the attenuation of neuron death was determined by evaluation of BDNF-TrkB-Akt-CREB signaling axis.

RESULTS

We showed that treatment with hUCB-MSCs attenuated neuronal loss and promoted neurogenesis in the hippocampus, an area highly vulnerable to IVH-induced brain injury. hUCB-MSCs activate BDNF-TrkB receptor signaling, eliciting intracellular activation of Akt and/or Erk and subsequent phosphorylation of CREB, which is responsible for promoting rat BDNF transcription. In addition to the beneficial effects of neuroprotection and neurogenesis, hUCB-MSCs also contribute to the restoration of impaired synaptic circuits in the hippocampus and improve neurocognitive functions in IVH-injured neonatal rat through BDNF-TrkB-CREB signaling axis activation.

CONCLUSIONS

Our data suggest that hUCB-MSCs possess therapeutic potential for treating neuronal loss and neurocognitive dysfunction in IVH through the activation of intracellular TrkB-CREB signaling that is invoked by hUCB-MSC-secreted BDNF.

Authors+Show Affiliations

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon, 16419, South Korea. Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 06351, South Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, 06351, South Korea.Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 06351, South Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, 06351, South Korea.Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon, 16419, South Korea. Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon, 16419, South Korea. Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea.Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, 06351, South Korea.Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 06351, South Korea. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea.Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 06351, South Korea. ws123.park@samsung.com. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. ws123.park@samsung.com. Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Seoul, 06351, South Korea. ws123.park@samsung.com.Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 2066, Seobu-ro, Jangan-gu, Suwon, 16419, South Korea. jeeahn@skku.edu. Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea. jeeahn@skku.edu. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwonro, Gangnam-gu, Seoul, 06351, South Korea. jeeahn@skku.edu. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. jeeahn@skku.edu. Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, 06351, South Korea. jeeahn@skku.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30463591

Citation

Ko, Hyo Rim, et al. "Human UCB-MSCs Treatment Upon Intraventricular Hemorrhage Contributes to Attenuate Hippocampal Neuron Loss and Circuit Damage Through BDNF-CREB Signaling." Stem Cell Research & Therapy, vol. 9, no. 1, 2018, p. 326.
Ko HR, Ahn SY, Chang YS, et al. Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling. Stem Cell Res Ther. 2018;9(1):326.
Ko, H. R., Ahn, S. Y., Chang, Y. S., Hwang, I., Yun, T., Sung, D. K., ... Ahn, J. Y. (2018). Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling. Stem Cell Research & Therapy, 9(1), p. 326. doi:10.1186/s13287-018-1052-5.
Ko HR, et al. Human UCB-MSCs Treatment Upon Intraventricular Hemorrhage Contributes to Attenuate Hippocampal Neuron Loss and Circuit Damage Through BDNF-CREB Signaling. Stem Cell Res Ther. 2018 11 21;9(1):326. PubMed PMID: 30463591.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human UCB-MSCs treatment upon intraventricular hemorrhage contributes to attenuate hippocampal neuron loss and circuit damage through BDNF-CREB signaling. AU - Ko,Hyo Rim, AU - Ahn,So Yoon, AU - Chang,Yun Sil, AU - Hwang,Inwoo, AU - Yun,Taegwan, AU - Sung,Dong Kyung, AU - Sung,Se In, AU - Park,Won Soon, AU - Ahn,Jee-Yin, Y1 - 2018/11/21/ PY - 2018/06/04/received PY - 2018/10/17/accepted PY - 2018/10/02/revised PY - 2018/11/23/entrez PY - 2018/11/23/pubmed PY - 2019/7/10/medline KW - BDNF KW - CREB KW - Hippocampus KW - Intraventricular hemorrhage KW - Mesenchymal stem cells SP - 326 EP - 326 JF - Stem cell research & therapy JO - Stem Cell Res Ther VL - 9 IS - 1 N2 - BACKGROUND: Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have been shown to prevent brain damage and improve neurocognition following intraventricular hemorrhage (IVH). However, the molecular mechanisms underlying the effects of hUCB-MSCs are still elusive. Thus, as the hippocampus is essential for learning, memory, and cognitive functions and is intimately involved in the ventricular system, making it a potential site of IVH-induced injury, we determined the molecular basis of the effects of hUCB-derived MSCs on hippocampal neurogenesis and the recovery of hippocampal neural circuits after IVH in a rodent model. METHODS: We inflicted severe IVH injury on postnatal day 4 (P4) in rats. After confirmation of successful induction of IVH using MRI (P5), intracerebroventricular administration of MSCs (ICV-MSC) was performed at 2 days post-injury (P6). For hippocampal synaptic determination, a rat entorhinal-hippocampus (EH) organotypic slice co-culture (OSC) was performed using day 3 post-IVH brains (P7) with or without ICV-MSCs. A similar strategy of experiments was applied to those rats receiving hUCB-MSC transfected with BDNF-Si-RNA for knockdown of BDNF or scrambled siRNA controls after IVH. The molecular mechanism of the MSCs effects on neurogenesis and the attenuation of neuron death was determined by evaluation of BDNF-TrkB-Akt-CREB signaling axis. RESULTS: We showed that treatment with hUCB-MSCs attenuated neuronal loss and promoted neurogenesis in the hippocampus, an area highly vulnerable to IVH-induced brain injury. hUCB-MSCs activate BDNF-TrkB receptor signaling, eliciting intracellular activation of Akt and/or Erk and subsequent phosphorylation of CREB, which is responsible for promoting rat BDNF transcription. In addition to the beneficial effects of neuroprotection and neurogenesis, hUCB-MSCs also contribute to the restoration of impaired synaptic circuits in the hippocampus and improve neurocognitive functions in IVH-injured neonatal rat through BDNF-TrkB-CREB signaling axis activation. CONCLUSIONS: Our data suggest that hUCB-MSCs possess therapeutic potential for treating neuronal loss and neurocognitive dysfunction in IVH through the activation of intracellular TrkB-CREB signaling that is invoked by hUCB-MSC-secreted BDNF. SN - 1757-6512 UR - https://www.unboundmedicine.com/medline/citation/30463591/Human_UCB_MSCs_treatment_upon_intraventricular_hemorrhage_contributes_to_attenuate_hippocampal_neuron_loss_and_circuit_damage_through_BDNF_CREB_signaling_ L2 - https://stemcellres.biomedcentral.com/articles/10.1186/s13287-018-1052-5 DB - PRIME DP - Unbound Medicine ER -