Tooth pulp as a source for neuronal precursor cells to study neurogenetic disorde

牙髓作为神经元前体细胞的来源来研究神经遗传疾病

• 批准号: 8413042
• 负责人: LAWRENCE T REITER
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413042
• 关键词: 15q; Alleles; Angelman Syndrome; Animal Model; Autistic Disorder; Autopsy; Biological Models; Biopsy; Brain; Cell Line; Cells; Cephalic; Characteristics; Cicatrix; DNA; Dental Pulp; Dentistry; Disabled Children; Disease; Distress; Epigenetic Process; Fibroblasts; Fragile X Syndrome; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Goals; Hereditary Disease; Human; Human Genetics; In Vitro; Ion Channel; Lead; Measures; Methods; Methylation; Modeling; Molecular; Mus; Neural Crest; Neural Crest Cell; Neurons; Pain; Pathogenesis; Patients; Pattern; Peripheral Nervous System; Physiological; Physiology; Property; Sampling; Skin; Source; Stem cells; Sum; Synapses; Syndrome; Testing; Therapeutic; Tissues; Tooth structure; Transcript; Transplantation; Viral Vector; autism spectrum disorder; autistic children; base; brain tissue; cell type; deciduous tooth; developmentally disabled; immunogenic; imprint; in vivo; insight; lymphoblast; mouse model; neurogenetics; neuron development; neurophysiology; novel strategies; precursor cell; protein expression; receptor; research study; stem

The study of neurogenetic disorders like Angelman, Rett and fragile X syndromes as well as autism spectrum disorders has depended largely on the analysis of gene/protein expression in non-neuronal biospecimens like lymphoblast and fibroblast cel lines. Although some analysis has been possible in post-mortem human brain tissue for neurogenetic syndromes, this tissue is often of variable quality and in limited amounts. Recently there has been an initiative to induce pluripotent stem cels (iPSCs) from patient fibroblasts and differentiate these iPSCs into various neuronal lineages. There are several problems with this approach: 1) fibroblasts must be obtained though a fairly invasive skin biopsy which leaves a scar and causes undue pain and distress in developmentally disabled or autistic children; 3) induction of fibroblasts into stem cells (reprogramming) and then into neuronal lineages is a laborious task that may not maintain epigenetic marks on the DNA that are essential to proper gene regulation in the native neuronal tissues; and 4) viral vectors which are themselves immunogenic are used to reprogram iPSCs limiting the downstream aplication of these neurons for therapeutic transplantations. Here we propose to use dental pulps from exfoliated primary teeth (EPT), as a source of stem cells for the study of a variety of neurogenetic syndromes. Dental pulp stem cells differentiate into functional neurons in vitro and in vivo. Dental pulps from EPT are also an easily obtainable source of cranial neural crest (CNC) cells. The majority of the cells in the peripheral nervous system, including neurons, are derived from the neural crest. Based on the extensive collaborative sum of our expertise in genetics, dental pulp stem cells and neurophysiology, we feel that this novel approach will provide a fresh perspective to the way we study expresion changes, epigenetics and neurophysiology in an ex-vivo model system for human neurogenetic disorders. !

神经遗传性疾病如Angelman、Rett和脆性X综合征的研究， 自闭症谱系障碍在很大程度上依赖于基因/蛋白质的分析， 在非神经元生物样本如淋巴母细胞和成纤维细胞系中表达。 尽管在死后的人脑组织中进行了一些分析， 神经遗传综合征，这种组织往往是可变的质量和数量有限。 最近，已经有一种从哺乳动物中诱导多能干细胞（iPSC）的倡议。 患者成纤维细胞并将这些iPSC分化成各种神经元谱系。那里 这种方法存在几个问题：1）成纤维细胞必须通过相当长的时间获得， 侵入性皮肤活检，留下疤痕，并导致过度的疼痛和痛苦， 发育障碍或自闭症儿童; 3）将成纤维细胞诱导成干细胞 （重编程）然后进入神经元谱系是一项艰巨的任务， 维持DNA上的表观遗传标记，这些标记对正常的基因调控至关重要。 天然神经元组织;和4）本身具有免疫原性的病毒载体， 用于重新编程iPSC，限制这些神经元的下游应用， 治疗性移植在这里，我们建议使用从脱落的牙髓 乳牙（EPT），作为干细胞的来源，用于研究各种神经发生 综合征牙髓干细胞体外诱导分化为功能性神经元的实验研究 vivo.来自EPT的牙髓也是颅神经嵴的容易获得的来源 (CNC)细胞周围神经系统中的大多数细胞，包括 神经元，是从神经嵴衍生出来的。基于广泛的合作总和， 我们在遗传学、牙髓干细胞和神经生理学方面的专业知识，我们认为， 一种新的方法将为我们研究表达的方式提供一个新的视角 在人的离体模型系统中的变化、表观遗传学和神经生理学 神经遗传性疾病 !

项目成果

Characterization of neurons from immortalized dental pulp stem cells for the study of neurogenetic disorders.

从永生化的牙髓干细胞中的神经元来研究神经遗传疾病。

• DOI: 10.1016/j.scr.2015.11.004
• 发表时间: 2015-11
• 期刊: Stem cell research
• 影响因子: 1.2
• 作者: Urraca N;Memon R;El-Iyachi I;Goorha S;Valdez C;Tran QT;Scroggs R;Miranda-Carboni GA;Donaldson M;Bridges D;Reiter LT
• 通讯作者: Reiter LT

Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons.

15Q重复的重大转录变化，但没有安吉尔曼综合征删除干细胞衍生的神经元。

• DOI: 10.1186/s13229-018-0191-y
• 发表时间: 2018
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Urraca N;Hope K;Victor AK;Belgard TG;Memon R;Goorha S;Valdez C;Tran QT;Sanchez S;Ramirez J;Donaldson M;Bridges D;Reiter LT
• 通讯作者: Reiter LT

Culturing and Neuronal Differentiation of Human Dental Pulp Stem Cells.

• DOI: 10.1002/cphg.28
• 发表时间: 2017-01-11
• 期刊: Current protocols in human genetics
• 作者: Goorha S;Reiter LT
• 通讯作者: Reiter LT

Effects of hTERT immortalization on osteogenic and adipogenic differentiation of dental pulp stem cells.

• DOI: 10.1016/j.dib.2016.01.009
• 发表时间: 2016-03
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Ikbale el-A;Goorha S;Reiter LT;Miranda-Carboni GA
• 通讯作者: Miranda-Carboni GA

A Rare Inherited 15q11.2-q13.1 Interstitial Duplication with Maternal Somatic Mosaicism, Renal Carcinoma, and Autism.

• DOI: 10.3389/fgene.2016.00205
• 发表时间: 2016
• 期刊: Frontiers in genetics
• 影响因子: 3.7
• 作者: Urraca N;Potter B;Hundley R;Pivnick EK;McVicar K;Thibert RL;Ledbetter C;Chamberlain R;Miravalle L;Sirois CL;Chamberlain S;Reiter LT
• 通讯作者: Reiter LT