Epigenetic regulation of neural stem cell differentiation towards spinal cord regeneration
Severe spinal cord injury (SCI) leads to almost complete neural cell loss at the injured site, causing the irreversible disruption of neuronal circuits. The transplantation of neural stem or precursor cells (NS/PCs) has been regarded as potentially effective for SCI treatment because NS/PCs can compensate for the injured sites by differentiating into neurons and glial cells (astrocytes and oligodendrocytes). An understanding of the molecular mechanisms that regulate the proliferation, fate specification and maturation of NS/PCs and their progeny would facilitate the establishment of better therapeutic strategies for regeneration after SCI. In recent years, several studies of SCI animal models have demonstrated that the modulation of specific epigenetic marks by histone modifiers and non-coding RNAs directs the setting of favorable cellular environments that promote the neuronal differentiation of NS/PCs and/or the elongation of the axons of the surviving neurons at the injured sites. In this review, we provide an overview of recent progress in the epigenetic regulation/manipulation of neural cells for the treatment of SCI.
KeywordsSpinal cord injury Neural stem/precursor cell Transplantation Epigenetics Neuronal regeneration
We thank Elizabeth Nakajima for editing the manuscript.
- Abematsu M, Tsujimura K, Yamano M, Saito M, Kohno K, Kohyama J, Namihira M, Komiya S, Nakashima K (2010) Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J Clin Invest 120:3255–3266CrossRefPubMedPubMedCentralGoogle Scholar
- Bjorklund LM, Sánchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 99:2344–2349CrossRefPubMedPubMedCentralGoogle Scholar
- Fujimoto Y, Abematsu M, Falk A, Tsujimura K, Sanosaka T, Juliandi B, Semi K, Namihira M, Komiya S, Smith A, Nakashima K (2012) Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells. Stem Cells 30:1163–1173CrossRefPubMedGoogle Scholar
- Goff LA, Groff AF, Sauvageau M, Trayes-Gibson Z, Sanchez-Gomez DB, Morse M, Martin RD, Elcavage LE, Liapis SC, Gonzalez-Celeiro M, Plana O, Li E, Gerhardinger C, Tomassy GS, Arlotta P, Rinn JL (2015) Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 112:6855–6862CrossRefPubMedPubMedCentralGoogle Scholar
- Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, Sundberg M, Moore MA, Perez-Torres E, Brownell AL, Schumacher JM, Spealman RD, Isacson O (2015) Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell 16:269–274CrossRefPubMedPubMedCentralGoogle Scholar
- Hon CC, Ramilowski JA, Harshbarger J, Bertin N, Rackham OJ, Gough J, Denisenko E, Schmeier S, Poulsen TM, Severin J, Lizio M, Kawaji H, Kasukawa T, Itoh M, Burroughs AM, Noma S, Djebali S, Alam T, Medvedeva YA, Testa AC, Lipovich L, Yip CW, Abugessaisa I, Mendez M, Hasegawa A, Tang D, Lassmann T, Heutink P, Babina M, Wells CA, Kojima S, Nakamura Y, Suzuki H, Daub CO, de Hoon MJ, Arner E, Hayashizaki Y, Carninci P, Forrest AR (2017) An atlas of human long non-coding RNAs with accurate 5′ ends. Nature 543:199-204CrossRefPubMedGoogle Scholar
- Kobayashi Y, Okada Y, Itakura G, Iwai H, Nishimura S, Yasuda A, Nori S, Hikishima K, Konomi T, Fujiyoshi K, Tsuji O, Toyama Y, Yamanaka S, Nakamura M, Okano H (2012) Pre-evaluated safe human iPSC-derived neural stem cells promote functional recovery after spinal cord injury in common marmoset without tumorigenicity. PLoS One 7:e52787CrossRefPubMedPubMedCentralGoogle Scholar
- Nagoshi N, Okano H (2017) Applications of induced pluripotent stem cell technologies in spinal cord injury. J Neurochem (in press)Google Scholar
- Rivieccio MA, Brochier C, Willis DE, Walker BA, D’Annibale MA, McLaughlin K, Siddiq A, Kozikowski AP, Jaffrey SR, Twiss JL, Ratan RR, Langley B (2009) HDAC6 is a target for protection and regeneration following injury in the nervous system. Proc Natl Acad Sci U S A 106:19599–19604CrossRefPubMedPubMedCentralGoogle Scholar
- Starkey ML, Davies M, Yip PK, Carter LM, Wong DJ, McMahon SB, Bradbury EJ (2009) Expression of the regeneration-associated protein SPRR1A in primary sensory neurons and spinal cord of the adult mouse following peripheral and central injury. J Comp Neurol 513:51–68CrossRefPubMedPubMedCentralGoogle Scholar
- Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R (2008) Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A 105:5856–5861CrossRefPubMedPubMedCentralGoogle Scholar
- Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, Moghadas Jafari A, Asady H, Razavi Tousi SM, Hosseini M (2016) Neural stem/progenitor cell transplantation for spinal cord injury treatment; a systematic review and meta-analysis. Neuroscience 322:377–397CrossRefPubMedGoogle Scholar