Direct reprogramming of epidermal cells to neural crest derivatives for cell therapies
Direct reprogramming of epidermal cells to neural crest derivatives for cell therapies
批准号:
9196190
负责人:
Stelios Theoharis Andreadis
金额:
$46.33万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-14 至 2020-06-30
关键词:
AdipocytesAdultAutologousBackBiological AssayCell TherapyCell TransplantationCellsChick EmbryoChickensChondrocytesCorpus CallosumDemyelinating DiseasesDevelopmentDiseaseEctodermEmbryoEpidermisEpigenetic ProcessFGF2 geneFibroblast Growth FactorFibroblast Growth Factor ReceptorsGene ExpressionGeneticGoldHumanLaboratoriesLifeLightMediatingMesenchymal Stem CellsModelingModificationMolecularMusNeonatalNeural CrestNeurodegenerative DisordersNeuronsOsteocytesPathway interactionsPeripheralProcessRegenerative MedicineRoleSchwann CellsShiveringSignal PathwaySignal TransductionSmooth Muscle MyocytesSourceSpinal Cord DiseasesStem cellsSystemTestingTherapeuticTransplantationWorkbasecell preparationcellular developmentdesignhigh throughput analysishuman diseaseimprovedinduced pluripotent stem cellinnovationkeratinocytekeratinocyte differentiationmelanocytemolecular arraymouse modelnovelnovel strategiespluripotencypostnatal humanregenerativeresearch studystem cell biologytranscription factor
中文摘要
摘要
我们的实验室最近发现,出生后的人表皮角质形成细胞(KC)可以重新编程
进入神经嵴(NC)的命运,而不遗传转录因子的引入或重编程,
多能国家KC衍生的NC(KC-NC)可诱导分化为所有功能性NC
包括外周神经元、黑素细胞、雪旺细胞和间充质干细胞衍生物的细胞衍生物
(骨细胞、软骨细胞、脂肪细胞和平滑肌细胞)。在移植到鸡胚胎中后,
KC-NC沿着沿着典型的途径迁移并产生多种NC衍生物。在此,我们建议
将我们的发现扩展到成人表皮角质形成细胞,提供对NC的机制理解,
重编程过程,并证明使用KC-NC衍生的雪旺细胞治疗
脱髓鞘疾病在aim 1中,我们将确定人成人表皮角质形成细胞是否可以被
在特定条件下重编程为神经嵴干细胞。目的2研究KC的作用机制
重新编程为NC命运。在目标3中,我们将制定一个高效的战略,使KC-NC与众不同,
雪旺氏细胞。KC-NC雪旺细胞将用于使用免疫抑制剂治疗脱髓鞘疾病。
先天性髓鞘生成不足疾病的小鼠模型已成为评估
髓鞘形成细胞制剂。这项工作代表了干细胞生物学的范式转变,因为它证明了
人类表皮细胞的可塑性被重新编程为共同发育起源的细胞,
来源于外胚层-没有遗传修饰,并在规定的培养条件下。最后我们
这项工作有可能提供一个新的来源,丰富,容易获得,自体干细胞
用于治疗神经退行性疾病,细胞来源仍然是严重的障碍
阻碍了细胞治疗方法。
英文摘要
ABSTRACT
Our laboratory recently discovered that postnatal human epidermal keratinocytes (KC) could be reprogrammed
into a neural crest (NC) fate without genetic introduction of transcription factors or reprogramming to the
pluripotent state. The KC-derived NC (KC-NC) could be coaxed to differentiate into all functional NC
derivatives including peripheral neurons, melanocytes, Schwann cells and mesenchymal stem cell derivatives
(osteocytes, chondrocytes, adipocytes and smooth muscle cells). Upon transplantation into chicken embryos,
KC-NC migrated along stereotypical pathways and gave rise to multiple NC derivatives. Here we propose to
extend our findings to adult epidermal keratinocytes, provide mechanistic understanding of the NC
reprograming process, and demonstrate the use of KC-NC derived Schwann cells for treatment of
demyelinating disease. In aim 1, we will determine whether human adult epidermal keratinocytes can be
reprogrammed into neural crest stem cells under defined conditions. Aim 2 will study the mechanism of KC
reprogramming into NC fate. In aim 3, we will develop a highly efficient strategy to differentiate KC-NC into
Schwann cells. The KC-NC Schwann cells will be employed for the treatment of demyelinating disease using a
mouse model of congenital hypomyelinating disease that has become the gold standard for the assessment of
myelinating cell preparations. This work represents a paradigm shift in stem cell biology as it demonstrates
the plasticity of human epidermal cells to be reprogrammed into cells of common developmental origin – both
originate from the ectoderm - without genetic modification and under defined culture conditions. Finally, our
work has the potential to provide a novel source of abundant, readily accessible, autologous stem cells
for treatment of neurodegenerative diseases, for which cell sourcing remains a severe impediment
hampering cell therapy approaches.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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海外基金