Uncovering the therapeutic potential of adipose tissue derived neural stem cells for Hirschsprung's disease.
揭示脂肪组织来源的神经干细胞治疗先天性巨结肠的潜力。
基本信息
- 批准号:10580052
- 负责人:
- 金额:$ 20.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipose tissueAffectBlood flowCell SeparationCellsCentral Nervous SystemClinicalClinical TrialsCoculture TechniquesColonColonic AganglionosisColorectalCompensationComplexCongenital MegacolonCongenital NeuropathyConstipationCuesDataDepositionDiseaseDoseEngraftmentEnteralEnteric Nervous SystemEnterocolitisEnvironmentExcisionFatty acid glycerol estersFecal IncontinenceFluorescence-Activated Cell SortingGangliaGastrointestinal tract structureGoalsHarvestHealthHumanIn VitroIntestinal SecretionsIntestinesInvestigationKnowledgeLaboratory cultureLifeLiquid substanceMethodsMicrosurgeryMorbidity - disease rateMovementMusNerve FibersNerve TissueNervous SystemNeurogliaNeuronsNeuropathyOperative Surgical ProceduresPatientsPhysiologicalPluripotent Stem CellsPopulationPostoperative ComplicationsPre-Clinical ModelProceduresProcessPropertyProtocols documentationRectumRegenerative MedicineReportingResearchResolutionRiskSchwann CellsScientific Advances and AccomplishmentsSignal TransductionSmooth MuscleSourceSuction LipectomySystemTherapeuticTissuesTransplantationVasomotoradipose derived stem cellcell motilityclinical applicationexperimental studyhuman stem cellshuman tissueimplantationin vivoinnovationinterestmigrationminimally invasivemouse modelnerve stem cellnervous system disorderneuralneurogenesisnovelpatient safetypostnatalpostnatal humanpreservationpreventrectalresponsesingle nucleus RNA-sequencingstem cell biomarkersstem cell migrationstem cell populationstem cell therapystem cellssubcutaneoustreatment strategytumorigenic
项目摘要
PROJECT SUMMARY
The overarching objective of our research is to develop a stem cell therapy from subcutaneous fat tissue
(SAT) to replace the congenitally absent enteric nervous system (ENS) in Hirschsprung disease (HSCR).
Surgical resection of the affected colon is currently the only viable treatment for HSCR. This is a necessary
life-saving procedure; albeit, more than 50% of patients still suffer from postoperative complications including
constipation, fecal incontinence, and enterocolitis. To overcome these morbidities, investigations into
treatments that can preserve the rectum and its functions are warranted. Replacement of the absent ENS via
stem cell therapies is touted as the most promising treatment strategy to achieve this goal. Our group has
demonstrated the feasibility of stem cell treatments by harvesting neural stem cells (NSCs) from the gut which
engraft, migrate and differentiate into neuronal networks when transplanted into mice with HSCR. For clinical
application this would require surgical resection of a piece of intestine. To prevent unnecessary resection
surgery, other sources of NSCs are of interest. Human fat (adipose) tissue contains a reservoir of stem cells
that are readily accessible. These cells have been examined in over 270 clinical trials for numerous diseases
that support favourable patient safety profiles. In our preliminary data we have also identified that nerve fiber
bundles from murine fat deposits – subcutaneous adipose tissue (SAT) - harbor an endogenous source of
NSCs that are unexplored for the treatment of neuropathies. We predict that the SAT could provide a useful
source of NSCs to treat colonic aganglionosis in HSCR; however, it remains undetermined if SAT-NSCs can
undergo neurogenesis in the aganglionic (absent ENS) environment of the gut and there are currently no
methods to purify and expand human SAT-NSCs. In the first aim of this study, we will determine if purified
SAT-NSCs from mice are capable of neurogenesis in aganglionic intestine. The ganglionated ENS is
supplemented postnatally by NSCs that migrate into the gut from extrinsic nerve fiber bundles and
differentiate into enteric neurons in response to environmental cues from the gut. We will address whether
SAT-NSCs can also undergo enteric neurogenesis when provided signalling cues from the ganglionic and
aganglionic gut in in vitro coculture systems and via microsurgical SAT-NSC implantation in vivo. To
determine how to isolate and expand human SAT-NSCs we will address the paucity of knowledge on the
origin of these cells. To accomplish this, cells isolated from human SAT nerve fiber bundles will be unbiasedly
characterised by single nuclei RNA-Seq before and after stem cell culture procedures. Cells expressing NSC
markers will be purified by fluorescence activated cell sorting and their differentiation potential will be
assessed in in vitro culture and in ex vivo transplants to the smooth muscle of the gut. The results of these
studies will establish procedures to isolate SAT-NSCs and assess their potential to treat the congenital
neuropathy in HSCR.
项目概要
我们研究的首要目标是开发皮下脂肪组织的干细胞疗法
(SAT)取代先天性缺失的先天性巨结肠症(HSCR)肠神经系统(ENS)。
手术切除受影响的结肠是目前 HSCR 唯一可行的治疗方法。这是必要的
救生程序;尽管如此,超过50%的患者仍然遭受术后并发症,包括
便秘、大便失禁和小肠结肠炎。为了克服这些疾病,需要进行调查
可以保护直肠及其功能的治疗是必要的。通过以下方式替换缺失的 ENS
干细胞疗法被誉为实现这一目标的最有希望的治疗策略。我们组有
证明了通过从肠道采集神经干细胞(NSC)进行干细胞治疗的可行性
当移植到具有 HSCR 的小鼠体内时,可移植、迁移并分化为神经元网络。用于临床
应用这需要手术切除一段肠道。为了防止不必要的切除
手术之外,其他来源的 NSC 也令人感兴趣。人体脂肪组织含有干细胞库
易于访问。这些细胞已在 270 多项针对多种疾病的临床试验中得到检验
支持良好的患者安全状况。在我们的初步数据中,我们还确定了神经纤维
来自小鼠脂肪沉积物的束——皮下脂肪组织(SAT)——含有内源性脂肪
尚未探索用于治疗神经病的神经干细胞。我们预测 SAT 可以提供有用的帮助
用于治疗 HSCR 中结肠无神经节细胞症的 NSC 来源;然而,SAT-NSC 是否可以
在肠道的无神经节(缺乏 ENS)环境中进行神经发生,目前还没有
纯化和扩增人类 SAT-NSC 的方法。在本研究的第一个目标中,我们将确定是否纯化
来自小鼠的 SAT-NSC 能够在无神经节肠中进行神经发生。神经节化 ENS 是
出生后通过从外在神经纤维束迁移到肠道的 NSC 进行补充
响应来自肠道的环境信号分化为肠神经元。我们将讨论是否
当来自神经节和神经节的信号线索提供时,SAT-NSC 也可以经历肠神经发生。
体外共培养系统中的无神经节肠和通过体内显微外科 SAT-NSC 植入。到
确定如何分离和扩展人类 SAT-NSC,我们将解决这方面知识的匮乏问题
这些细胞的起源。为了实现这一目标,从人类 SAT 神经纤维束中分离出的细胞将被公正地
通过干细胞培养程序之前和之后的单核 RNA 测序进行表征。表达 NSC 的细胞
标记物将通过荧光激活细胞分选进行纯化,并且它们的分化潜力将是
在体外培养和离体移植到肠道平滑肌中进行评估。这些结果
研究将建立分离 SAT-NSC 的程序并评估其治疗先天性
HSCR 中的神经病变。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bone Marrow Stem Cells Derived from Nerves Have Neurogenic Properties and Potential Utility for Regenerative Therapy.
- DOI:10.3390/ijms24065211
- 发表时间:2023-03-08
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
Schwann cells in the subcutaneous adipose tissue have neurogenic potential and can be used for regenerative therapies.
- DOI:10.1126/scitranslmed.abl8753
- 发表时间:2022-05-25
- 期刊:
- 影响因子:17.1
- 作者:
- 通讯作者:
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ALLAN M GOLDSTEIN其他文献
ALLAN M GOLDSTEIN的其他文献
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{{ truncateString('ALLAN M GOLDSTEIN', 18)}}的其他基金
Uncovering the therapeutic potential of adipose tissue derived neural stem cells for Hirschsprung's disease.
揭示脂肪组织来源的神经干细胞治疗先天性巨结肠的潜力。
- 批准号:
10452149 - 财政年份:2022
- 资助金额:
$ 20.62万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
9895033 - 财政年份:2020
- 资助金额:
$ 20.62万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
10066349 - 财政年份:2020
- 资助金额:
$ 20.62万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
10319974 - 财政年份:2020
- 资助金额:
$ 20.62万 - 项目类别:
Characterizing neurogenic progenitors in the adult intestine
成人肠道神经源性祖细胞的特征
- 批准号:
10545000 - 财政年份:2020
- 资助金额:
$ 20.62万 - 项目类别:
Development of the Enteric Nervous System: Cells, Signals, Genes, and Therapy
肠神经系统的发育:细胞、信号、基因和治疗
- 批准号:
9541099 - 财政年份:2018
- 资助金额:
$ 20.62万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠肠神经系统发育
- 批准号:
8464065 - 财政年份:2009
- 资助金额:
$ 20.62万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠肠神经系统发育
- 批准号:
8277360 - 财政年份:2009
- 资助金额:
$ 20.62万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠神经系统发育
- 批准号:
7730368 - 财政年份:2009
- 资助金额:
$ 20.62万 - 项目类别:
Gdnf and endothelin-3 regulate colorectal enteric nervous system development
Gdnf 和内皮素 3 调节结直肠肠神经系统发育
- 批准号:
8072025 - 财政年份:2009
- 资助金额:
$ 20.62万 - 项目类别:
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