Use of umbilical cord as a unique stem cell source for tissue regeneration

使用脐带作为组织再生的独特干细胞来源

• 批准号: 8391556
• 负责人: XIAO-DONG CHEN
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391556
• 关键词: Adhesions; Adipocytes; Adult; Aging; Agreement; Alternative Therapies; Animal Model; Blood Vessels; Bone Marrow Cells; Cardiac; Cardiac Myocytes; Cell Lineage; Cell Therapy; Cell-Matrix Junction; Cells; Cessation of life; Chondroblast; Clinical; Data; Development; Disease; Ectoderm; Embryo; Endoderm; Extracellular Matrix; Fatty acid glycerol esters; Gene Expression; Germ Layers; Gland; Goals; Graft Rejection; Health; Heart; Heart Transplantation; Heart failure; Hepatocyte; Human; Immunocompromised Host; In Vitro; Intestines; Marrow; Mesenchymal Stem Cells; Mesoderm; Microarray Analysis; Mononuclear; Mus; Muscle; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Nerve; Nerve Fibers; Osteoblasts; Outcome Study; Paper; Plastics; Population; Positioning Attribute; Procedures; Property; Reliance; Reporting; Research; Retrieval; Signal Transduction; Source; Stem Cell Development; Stem cells; Surveys; System; Teratoma; Testing; Therapeutic; Tissues; Transplantation; Umbilical Cord Blood; Umbilical cord structure; Veterans; age related; angiogenesis; base; bone; clinical application; heart function; human embryonic stem cell; implantation; improved; in vivo; innovation; mouse model; novel therapeutic intervention; public health relevance; reconstruction; repaired; self-renewal; tissue regeneration

DESCRIPTION (provided by applicant): Human umbilical cord blood (UCB) contains mesenchymal stem cells (MSCs) that have higher multipotentiality than adult marrow-derived MSCs (BM-MSCs). However, these cells have been difficult to obtain because the number of MSCs in UCB is extremely low (~5 to 30 out of 1 x 108 mononuclear cells). To date, the isolation of MSCs has depended upon their plastic-adhesion capacity. Most extremely immature MSCs in UCB are likely missed because their ability to adhere to plastic is poor. Our previous studies demonstrated that cellular extracellular matrix (ECM) made by bone marrow cells enhanced MSC attachment and proliferation, and retained their stem cell properties (Chen, et al, 2007, JBMR, 22:1943). Using this system, we found that human UCB may contain a large number of MSCs that adhere to the ECM (at least 10,000- to 100,000-fold greater than that previously reported), but not to plastic. More importantly, implantation of UCB-derived MSCs (UCB-MSCs) obtained by ECM adhesion into immunocompromised mice generated 3 embryonic germ layers-derived tissues including bone, muscle, fat, gland, intestine and nerve fibers. Encouraged by these findings, we propose the hypothesis that human UCB contains a large number of embryonic-like stem cells that have the potential to be used for tissue regeneration in general and myocardial reconstruction in particular. To test this hypothesis, the following 3 Specific Aims will be pursued: Specific Aim 1 is to determine the similarities and differences in global gene expression among human embryonic stem cells (hES cells), UCB-MSCs isolated by ECM adhesion versus those isolated by plastic adhesion, and human adult BM-MSCs, using microarray technology. Specific Aim 2 is to determine the ability of human UCB-MSCs obtained by ECM adhesion to selectively differentiate into desired cell lineages originated from 3 embryonic germ layers in vitro under conditions known to induce commitment to a specific cell lineage, including osteoblasts, adipocytes, chondroblasts and cardiomyocytes (mesoderm), nerve (ectoderm) and hepatocytes (endoderm). Specific Aim 3 is to evaluate the capability of transplanted UCB-MSCs obtained by the ECM adhesion to improve heart function after myocardial infarction (MI) using a well-established mouse model. Despite the great developmental potential of hES cells, there appears to be widespread agreement that a less critical source of cellular material would be preferable for the clinical use of tissue regeneration. If the proposed studies confirm that ECM can enhance retrieval of large numbers of embryonic-like stem cells from UCB, the resulting unlimited source of highly functional UCB-derived MSCs would make it feasible to be alternative to hES cells for cell-based clinical application. Specially, the ultimate outcome of these studies may be a highly practical stem cell- based therapy to treat the post-MI veteran.

描述（由申请人提供）： 人脐带血（UCB）含有比成人骨髓衍生的MSC（BM-MSC）更高的多能性的间充质干细胞（MSC）。但是，这些细胞很难获得，因为UCB中的MSC数量极低（1 x 108个单核细胞中的5至30）。迄今为止，MSC的隔离取决于它们的塑料粘附能力。 UCB中最不成熟的MSC可能会错过，因为它们粘附在塑料的能力很差。我们先前的研究表明，由骨髓细胞制造的细胞外基质（ECM）增强了MSC附着和增殖，并保留了其干细胞特性（Chen等，2007，JBMR，22：1943）。使用该系统，我们发现人UCB可能包含大量遵守ECM的MSC（至少比以前报道的至少10,000至100,000倍），但不适合塑料。更重要的是，通过ECM粘附在免疫受损小鼠中获得的UCB衍生的MSC（UCB-MSC）植入，产生了3种胚胎细菌衍生的组织，包括骨，肌肉，肌肉，脂肪，脂肪，腺，肠，肠和神经纤维。在这些发现的鼓励下，我们提出了这样一个假设，即人UCB包含大量胚胎样干细胞，这些干细胞有可能用于组织再生，尤其是心肌重建。为了检验这一假设，将追求以下3个特定目标：具体目的1是确定人类胚胎干细胞（HES细胞）之间的全球基因表达的相似性和差异，通过ECM粘附分离的UCB-MSC与塑料粘附分离的uCB-MSC，以及使用微阵列技术的人类BM-MSC分离的相似性和差异。具体目的2是确定通过ECM粘附获得的人类UCB-MSC的能力，以选择性地分化为所需的细胞谱系，起源于在已知诱导特定细胞谱系承诺的条件下，体外的3个胚胎细菌层，包括成骨细胞，包括成骨细胞，脂肪细胞，软骨细胞和心脏植物（Mosocyocytes）（Mosocymocipyers）（Mosocysery）（Mesodercy）（Mosodercy）（Mosodercy）（Mosofersecters）（Mesocters）（Mosof）（毛s）（Mosof）（Mosof）（毛s）（毛孔）（毛状）（毛孔），（毛状）（毛孔）（毛孔） （内胚层）。具体目的3是使用良好的小鼠模型评估通过ECM粘附获得的移植的UCB-MSC的能力，以改善心肌梗死（MI）后心脏功能。 尽管HES细胞具有巨大的发育潜力，但似乎普遍同意的是，细胞材料的关键来源对于组织再生的临床使用是可取的。如果拟议的研究证实，ECM可以从UCB中提高大量胚胎样干细胞的检索，则最终功能高度功能的UCB衍生的MSC的无限来源将使可以在基于细胞的临床应用中替代HES细胞。特别是，这些研究的最终结果可能是一种高度实用的基于干细胞的治疗，用于治疗MI后退伍军人。