KDM2B and its peptides promote the stem cells from apical papilla mediated nerve injury repair in rats by intervening EZH2 function

Abstract

How to improve the neurogenic potential of mesenchymal stem cells (MSCs) and develop biological agent based on the underlying epigenetic mechanism remains a challenge. Here, we investigated the effect of histone demethylase Lysine (K)-specific demethylase 2B (KDM2B) on neurogenic differentiation and nerve injury repair by using MSCs from dental apical papilla (SCAP). We found that KDM2B promoted the neurogenic indicators expression and neural spheres formation in SCAP, and modified the Histone H3K4 trimethylation (H3K4me3) methylation on neurogenesis-related genes. KDM2B improved the SCAP mediated recovery of motor ability at the early healing stage of spinal cord injury rats. Meanwhile, KDM2B acted as a negative regulator to its partner EZH2 during neurogenic differentiation, enhancer of zeste homologue 2 (EZH2) suppressed the neurogenic ability of SCAP. Further, the protein interaction between KDM2B and EZH2 was identified which decreased during neurogenic differentiation. On this basis, we revealed seven key protein binding sequences of KDM2B to EZH2, and synthesized KDM2B-peptides based on these sequences. By the usage of KDM2B-peptides, EZH2 function was effectively intervened and the neurogenic ability of SCAP was promoted. More, KDM2B-peptides significantly improved the SCAP mediated functional recovery at SCI early phase. Our study revealed that KDM2B acted as a promotor to neurogenic differentiation ability of dental MSCs through binding and negatively regulating EZH2, and provided the KDM2B-peptides as candidate agents for improving the neurogenic ability of MSCs and nerve injury repair.

References

[1] GilbertEAB, Lakshman N, LauKSK, MorsheadCM. Regulating endogenous neural stem cell activation to promote spinal cord injury repair. Cells. 2022;11:846.

[2] XuX, LiangZ, LinY, et al. Comparing the efficacy and safety of cell transplantation for spinal cord injury: a systematic review and Bayesian network meta-analysis. Front Cell Neurosci. 2022;16:860131.

[3] Van den BosJ, Ouaamari YE, WoutersK, CoolsN, WensI. Are cell-based therapies safe and effective in the treatment of neurodegenerative diseases? A systematic review with meta-analysis. Biomolecules. 2022;12:340.

[4] HejratiN, Fehlings MG. A review of emerging neuroprotective and neuroregenerative therapies in traumatic spinal cord injury. Curr Opin Pharmacol. 2021;60:331-340.

[5] BadhiwalaJH, WilsonJR, WitiwCD, et al. The influence of timing of surgical decompression for acute spinal cord injury: a pooled analysis of individual patient data. Lancet Neurol. 2021;20:117-126.

[6] Martin-LopezM, Fernandez-Muñoz B, CanovasS. Pluripotent stem cells for spinal cord injury repair. Cells. 2021;10:3334.

[7] AndersonKD, GuestJD, DietrichWD, et al. Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma. 2017;34:2950-2963.

[8] BartlettRD, BurleyS, IpM, Phillips JB, ChoiD. Cell therapies for spinal cord injury: trends and challenges of current clinical trials. Neurosurgery. 2020;87:E456-E472.

[9] SuzukiH, SakaiT. Current concepts of stem cell therapy for chronic spinal cord injury. Int J Mol Sci. 2021;22:7435.

[10] VaqueroJ, ZuritaM, RicoMA, et al. Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. Cytotherapy. 2017;19:349-359.

[11] YangY, PangM, DuC, et al. Repeated subarachnoid administrations of allogeneic human umbilical cord mesenchymal stem cells for spinal cord injury: a phase 1/2 pilot study. Cytotherapy. 2021;23:57-64.

[12] CurtA, HsiehJ, SchubertM, et al. The damaged spinal cord is a suitable target for stem cell transplantation. Neurorehabil Neural Repair. 2020;34:758-768.

[13] CurtisE, MartinJR, GabelB, et al. A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury. Cell Stem Cell. 2018;22:941-950.e6.

[14] LeviAD, Anderson KD, OkonkwoDO, et al. Clinical outcomes from a multi-center study of human neural stem cell transplantation in chronic cervical spinal cord injury. J Neurotrauma. 2019;36:891-902.

[15] De BerdtP, Vanvarenberg K, UcakarB, et al. The human dental apical papilla promotes spinal cord repair through a paracrine mechanism. Cell Mol Life Sci. 2022;79:252.

[16] ChoiJR, YongKW, NamHY. Current status and perspectives of human mesenchymal stem cell therapy 2020. Stem Cells Int. 2022;2022:9801358.

[17] HataM, OmiM, KobayashiY, et al. Transplantation of human dental pulp stem cells ameliorates diabetic polyneuropathy in streptozotocin-induced diabetic nude mice: the role of angiogenic and neurotrophic factors. Stem Cell Res Ther. 2020;11:236.

[18] WangD, WangY, TianW, Pan J. Advances of tooth-derived stem cells in neural diseases treatments and nerve tissue regeneration. Cell Prolif. 2019;52:e12572.

[19] ZhangC, YeW, ZhaoM, Long L, XiaD, FanZ. KDM6B negatively regulates the neurogenesis potential of apical papilla stem cells via HES1. Int J Mol Sci. 2023;24:10608.

[20] ZhuY, ZhangP, GuRL, LiuYS, ZhouSY. Origin and clinical applications of neural crest-derived dental stem cells. Chin J Dent Res. 2018;21:89-100.

[21] ZhangC, YeW, ZhaoM, Long L, XiaD, FanZ. MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1. Int J Oral Sci. 2023;15:48.

[22] AngelovaMT, Dimitrova DG, DingesN, et al. The emerging field of Epitranscriptomics in neurodevelopmental and neuronal disorders. Front Bioeng Biotechnol. 2018;6:46.

[23] LewerissaEI, Nadif Kasri N, LindaK. Epigenetic regulation of autophagy-related genes: implications for neurodevelopmental disorders. Autophagy. 2024;20:15-28.

[24] SharmaS, BhondeR. Applicability of mesenchymal stem cell-derived exosomes as a cell-free miRNA therapy and epigenetic modifiers for diabetes. Epigenomics. 2023;15:1323-1336.

[25] van JaarsveldRH, ReillyJ, CornipsMC, et al. Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature. Genetics in medicine: official journal of the American College of Medical. Genetics. 2023;25:49-62.

[26] DomiziP, Malizia F, Chazarreta-CifreL, DiacovichL, Banchio C. KDM2B regulates choline kinase expression and neuronal differentiation of neuroblastoma cells. PLoS One. 2019;14:e0210207.

[27] LiW, ShenW, ZhangB, et al. Long non-coding RNA LncKdm2b regulates cortical neuronal differentiation by cis-activating Kdm2b. Protein Cell. 2020;11:161-186.

[28] FukudaT, Tokunaga A, SakamotoR, YoshidaN. Fbxl10/Kdm2b deficiency accelerates neural progenitor cell death and leads to exencephaly. Mol Cell Neurosci. 2011;46:614-624.

[29] KimN, ByunS, UmSJ. Additional sex combs-like family associated with epigenetic regulation. Int J Mol Sci. 2024;25:5119.

[30] LiH, LaiP, JiaJ, et al. RNA helicase DDX5 inhibits reprogramming to pluripotency by miRNA-based repression of RYBP and its PRC1-dependent and -independent functions. Cell Stem Cell. 2017;20:571.

[31] KuangY, XuH, LuF, et al. Inhibition of microRNA let-7b expression by KDM2B promotes cancer progression by targeting EZH2 in ovarian cancer. Cancer Sci. 2021;112:231-242.

[32] DeiktakisEE, AbramsM, TsaparaA, et al. Identification of structural elements of the lysine specific demethylase 2B CxxC domain associated with replicative senescence bypass in primary mouse cells. Protein J. 2020;39:232-239.

[33] TzatsosA, PfauR, KampranisSC, Tsichlis PN. Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci U S A. 2009;106:2641-2646.

[34] CaoY, ShiR, YangH, et al. Epiregulin promotes osteogenic differentiation and inhibits neurogenic trans-differentiation of adipose-derived mesenchymal stem cells via MAPKs pathway. Cell Biol Int. 2020;44:1046-1058.

[35] FanZP, YamazaT, LeeJS, et al. BCOR regulates mesenchymal stem cell function by epigenetic mechanisms. Nat Cell Biol. 2009;11:1002-1009.

[36] GageFH. Adult neurogenesis in neurological diseases. Science. 2021;374:1049-1050.

[37] PushchinaEV, Kapustyanov IA, KlukaGG. Adult neurogenesis of teleost fish determines high neuronal plasticity and regeneration. Int J Mol Sci. 2024;25:3658.

[38] LeeHR, LeeJ, KimHJ. Differential effects of MEK inhibitors on rat neural stem cell differentiation: repressive roles of MEK2 in neurogenesis and induction of astrocytogenesis by PD98059. Pharmacol Res. 2019;149:104466.

[39] HuygheA, FurlanG, OzmadenciD, et al. Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling. Nat Cell Biol. 2020;22:389-400.

[40] SelleriL, Zappavigna V, FerrettiE. ’Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks. Genes Dev. 2019;33:258-275.

[41] XuHY, SunYJ, SunYY, et al. Lapatinib alleviates TOCP-induced axonal damage in the spinal cord of mouse. Neuropharmacology. 2021;189:108535.

[42] WuSH, LiaoYT, HuangCH, Chen YC, ChiangER, WangJP. Comparison of the confluence-initiated neurogenic differentiation tendency of adipose-derived and bone marrow-derived mesenchymal stem cells. Biomedicine. 2021;9:1503.

[43] HornZ, Behesti H, HattenME. N-cadherin provides a cis and trans ligand for astrotactin that functions in glial-guided neuronal migration. Proc Natl Acad Sci U S A. 2018;115:10556-10563.

[44] LvB, ZhangX, YuanJ, et al. Biomaterial-supported MSC transplantation enhances cell-cell communication for spinal cord injury. Stem Cell Res Ther. 2021;12:36.

[45] PangQM, ChenSY, XuQJ, et al. Neuroinflammation and scarring after spinal cord injury: therapeutic roles of MSCs on inflammation and glial scar. Front Immunol. 2021;12:751021.

[46] RibeiroBF, da Cruz BC, de SousaBM, et al. Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential. Brain. 2023;146:2672-2693.

[47] ElkhenanyH, Bonilla P, GiraldoE, et al. A hyaluronic acid Demilune scaffold and Polypyrrole-coated fibers carrying embedded human neural precursor cells and curcumin for surface capping of spinal cord injuries. Biomedicine. 2021;9:1928.

[48] ZahaviEE, Hoogenraad CC. Multiple layers of spatial regulation coordinate axonal cargo transport. Curr Opin Neurobiol. 2021;69:241-246.

[49] GhanavatinejadF, Fard Tabrizi ZP, OmidghaemiS, SharifiE, Møller SG, JamiMS. Protein biomarkers of neural system. J Otol. 2019;14:77-88.

[50] GengX, ZouY, LiS, et al. Electroacupuncture promotes the recovery of rats with spinal cord injury by suppressing the notch signaling pathway via the H19/EZH2 axis. Ann Transl Med. 2021;9:844.

[51] HongF, ZhaoM, ZhangL, Feng L. Inhibition of Ezh2 in vitro and the decline of Ezh2 in developing midbrain promote dopaminergic neurons differentiation through modifying H3K27me3. Stem Cells Dev. 2019;28:649-658.

[52] JiangW, ZhangS, LaiQ, FangY, WangM. Stat3-induced lncRNA Kcnq1ot1 regulates the apoptosis of neuronal cells in spinal cord injury. J Mol Neurosci. 2022;72:610-617.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.