Alveolar Bone Marrow Derived Stem Cells for Clinical Cell Therapy

用于临床细胞治疗的肺泡骨髓干细胞

基本信息

批准号：
8733350
负责人：
DARNELL KAIGLER
金额：
$ 31.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-25 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8733350
关键词：
Address Animals Autologous Autologous Transplantation Back Biological Models Biology Biopsy Blood Vessels Bone Marrow Bone Regeneration Bone Tissue Cell Count Cell Proliferation Cell Separation Cell Therapy Cell surface Cells Characteristics Clinical Complex Congenital Disorders Culture Media Data Defect Deformity Dental Care Development Disease ENG gene Growth Factor Harvest Head and neck structure Healthcare Hip region structure Human In Vitro Individual Investigation Jaw Link Measures Mesenchymal Stem Cells Methodology Methods Modeling Mus Natural regeneration Nature Osteogenesis Outcome Outcome Measure PTPRC gene Phenotype Population Practice Guidelines Procedures Production Property Rattus Regenerative Medicine Rehabilitation therapy Safety Sampling Serum Site Source Stem cells Surrogate Markers System Techniques Telomerase Testing Therapeutic Tissues Tooth Extraction Transplantation Trauma Treatment Effectiveness Tumorigenicity alveolar bone base bone cell type clinically relevant craniofacial human subject in vivo insight pre-clinical preclinical study public health relevance reconstruction regenerative regenerative therapy self-renewal skeletal stem cell biology stem cell population subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Cell therapy holds significant potential for the reconstruction and regeneration of craniofacial defects and deformities. One of the most important aspects of cell therapy is the identification of the most appropriate cell source for isolation of cells. Historically, mesenchymal stem cells (MSCs) derived from bone marrow have demonstrated regenerative potential in many preclinical studies. However, traditional techniques for isolating MSCs typically involve a bone marrow harvest from the iliac crest. Due to the invasive nature of the iliac crest bone marrow harvest procedure and the developmental (endochondral) origin of this tissue, it would be far more desirable to have a more readily accessible and developmentally similar (intramembranous) source of MSCs for craniofacial therapeutic indications. To this end, we have preliminary evidence which suggests that MSCs can be predictably isolated from alveolar bone marrow, using a simple, standardized, reproducible technique. Our hypothesis is that using current Good Manufacturing Practices (cGMP) guidelines, alveolar bone marrow derived MSCs (aBMSCs) can be safely expanded ex vivo, to numbers sufficient for autogenous clinical transplantation in human craniofacial bone defects. Additionally, we hypothesize that in vitro and preclinical surrogate markers exist which can be predictive of clinical regenerative outcomes. To test these hypotheses, the project proposed has three Specific Aims (SAs). In SA1, we will isolate, expand, and phenotypically characterize populations of alveolar bone marrow derived stem cells from 30 different human subjects. SA2 will evaluate the preclinical bone regenerative potential of aBMSCs in vivo using ectopic and clinically relevant orthotopic model systems. Finally, in SA3, following autologous transplantation of aBMSCs into human craniofacial bone defects, we will determine how the phenotypic characteristics of different aBMSC populations correlate to their respective capacities to regenerate bone in vivo and clinically. Key outcome measures include: phenotypic characterization of aBMSCs; in vivo potential of aBMSCs to regenerate bone and vascular tissue; safety of aBMSC cell isolation and expansion methodologies for human application; clinical potential of aBMSCs to regenerate bone and vascular tissue; and examination of correlations between in vitro phenotype, in vivo bone regeneration, and clinical bone regeneration. Findings of the proposed study could significantly advance clinical cell therapy approaches for craniofacial regeneration. Additionally, the isolation of aBMSCs with the technique employed would have broad scientific impact in providing an alternative source of MSCs to be used in fundamental investigations of stem cell and bone biology.

描述（由申请人提供）：细胞疗法对于颅面缺陷和畸形的重建和再生具有巨大的潜力。细胞治疗最重要的方面之一是鉴定用于分离细胞的最合适的细胞来源。从历史上看，源自骨髓的间充质干细胞（MSC）在许多临床前研究中已证明具有再生潜力。然而，分离 MSC 的传统技术通常涉及从髂嵴采集骨髓。由于髂嵴骨髓采集程序的侵入性以及该组织的发育（软骨内）起源，因此更需要一种更容易获得且发育相似（膜内）的 MSC 来源用于颅面治疗适应症。为此，我们有初步证据表明可以使用简单、标准化、可重复的技术从肺泡骨髓中分离出间充质干细胞。我们的假设是，使用当前的良好生产规范（cGMP）指南，牙槽骨髓源性间充质干细胞（aBMSCs）可以安全地离体扩增，达到足以用于人类颅面骨缺损的自体临床移植的数量。此外，我们假设存在体外和临床前替代标记，可以预测临床再生结果。为了检验这些假设，该项目提出了三个具体目标 (SA)。在 SA1 中，我们将分离、扩增来自 30 名不同人类受试者的肺泡骨髓干细胞群，并对其进行表型表征。 SA2将使用异位和临床相关的原位模型系统评估aBMSC在体内的临床前骨再生潜力。最后，在 SA3 中，将 aBMSC 自体移植到人颅面骨缺损中后，我们将确定不同 aBMSC 群体的表型特征如何与其各自体内和临床骨再生能力相关。主要结果指标包括： aBMSC 的表型特征； aBMSC 体内再生骨和血管组织的潜力； aBMSC 细胞分离和扩增方法用于人类应用的安全性； aBMSC 再生骨和血管组织的临床潜力；并检查体外表型、体内骨再生和临床骨再生之间的相关性。拟议研究的结果可以显着推进颅面再生的临床细胞治疗方法。此外，使用所采用的技术分离 aBMSC 将产生广泛的科学影响，为干细胞和骨生物学的基础研究提供替代的 MSC 来源。