Repair of Bone Defects with Human Autologous Pluripotent Very Small Embryonic lik

描述(申请人提供)：在美国，由于骨折和疾病导致的骨丢失是一种严重的疾病，影响着数百万美国人。尤其是口语方面的问题。 颅面部疾病是指每年治疗损伤的费用超过600亿美元。此外，牙周炎与系统性疾病有关，如糖尿病、早产儿低出生体重和心血管疾病。虽然人们已经做出了很大的努力来了解大骨的愈合机制和开发治疗全面性骨丢失的治疗方法，但关于人类颅面骨骼的骨重塑和颌骨骨坏死的机制的信息很少，也几乎没有有效的治疗方法。我们的第一阶段SBIR的结果表明，一个独特的人，成人，多能，非常小的胚胎样干细胞(VSEL)群体，具有重要的骨再生特性，可用于治疗口腔颅面疾病。人VSEL是一种多能干细胞，参与组织的正常更新和再生，其循环水平在损伤后显著增加。它们能够修复心肌梗死后受损的组织，如心脏。成人VSEL是SSEA-4+/OCT-4+/CD133+/CXCR4+/LIN-/CD45-，表达多潜能标记(Oct-4和Nanog)，能够分化为来自三个生殖系的细胞。与我们的合作者密歇根大学的Russell Taichman博士一起，我们展示了VSEL在骨髓内移植后分化为成骨细胞系。重要的是，来自成人的VSEL修复了SCID小鼠的颅骨缺陷。U-CT扫描显示，人VSEL在损伤部位形成新骨，组织学分析显示成骨、新骨形成、骨小梁致密增厚和骨髓形成。最重要的是，新的骨组织是从人类VSEL中衍生出来的。这些研究表明，VSEL可以生成新骨，并具有修复骨骼损伤的潜力。在这个第二阶段的SBIR中，我们建议进一步测试人类VSEL在人类患者身上再生骨的有效性。具体地说，我们将测试VSEL促进人类头面部骨骼骨重塑的能力。在我们的研究中，我们将在一个拔牙模型中测试人类VSEL在人类身上生成骨骼的效果，在该模型中，由于龋齿或牙周病而需要拔牙的人将成为研究对象。在这些人中，潜在的颌骨组织会受到损伤和耗尽，虽然拔牙后会有一些愈合时间，但过程是缓慢的。我们将测试从患者身上分离出来的VSEL在拔牙后是否会加速口腔中的骨骼生长。VSEL是自体的，不会引起排斥反应，不会形成肿瘤或造成其他健康风险。这不是一项临床试验，而是一项以患者为中心的研究，旨在推动VSEL作为骨修复治疗的发展。如果成功，这些研究将为VSEL的快速临床开发提供基础，用于颅面骨再生和治疗其他一些基于骨骼的疾病。 公共卫生相关性：NeoStem的目标是开发人类VSEL的治疗能力，以治疗一系列疾病和障碍。这项提案中的研究重点是建立VSEL在修复骨骼和治疗口腔-颅面疾病方面的效用。如果在人类身上的这些研究结果显示成人自体VSEL在骨修复中的安全性和有效性，那么我们将尝试在未来的临床研究中进一步开发这种细胞疗法，以建立细胞作为治疗骨疾病和骨丢失的标准护理。

DESCRIPTION (provided by applicant): Bone loss due to fractures and disease is a serious medical condition in the US affecting millions of Americans. It is particularly a problem with oral craniofacial disorders were the costs of treating damage exceeds $60 billion annually. Furthermore, periodontitis is associated with systemic disorders such as diabetes mellitus, preterm low birth weight, and cardiovascular disease. While major efforts have been made to understand mechanisms of healing of large bones and to develop therapeutics to treat overall bone loss, very little information is available on bone remodeling in the human craniofacial skeleton, nor the mechanisms involved in osteonecrosis of the jaw and there are few effective treatments. The results of our phase 1 SBIR showed that a unique population of human, adult, pluripotent, Very Small Embryonic like (VSEL) stem cells, have important bone regenerative properties and could be useful in treating oral-craniofacial disorders. Human VSELs are pluripotent stem cells involved in the normal turnover and regeneration of tissues and their circulating levels greatly increase in response to injury. They are able to repair injured tissues such as the heart after myocardial infarct. Adult human VSELs, are SSEA-4+/Oct-4+/CD133+/CXCR4+/Lin-/CD45-, express pluripotency markers (Oct-4 and Nanog) and are capable of differentiation into cells from all three germ lineages. With our collaborator, Dr. Russell Taichman of the University of Michigan we showed that VSELs differentiate to osteoblastic lineage after intra-marrow transplant. Importantly, VSELs from adult humans repaired a calvarial defect in SCID mice. The human VSELs formed new bone when applied in the injured area as measured by u-CT scan, and histological analysis demonstrated osteogeneis, significant new bone formation, dense thickening of the trabeculae and bone marrow formation. Most importantly, new bone tissue was derived from the human VSELs. These studies show that VSELs can generate new bone and have the potential to repair bone injuries. In this phase 2 SBIR, we propose to further test the effectiveness of human VSELs to regenerate bone in human patients. Specifically, we will test the ability of VSELs to promote bone remodeling in the human craniofacial skeleton. For our studies, we will test the efficacy of human VSELs to generate bone in humans in a tooth extraction model in which individuals requiring tooth extraction due to caries or periodontal disease will be the subjects. In these individuals, the underlying jaw bone tissue is injured and depleted and while there is some healing overtime after tooth extraction, the process is slow. We will test whether VSELs isolated from the patient expedite bone growth in the oral cavity after tooth removal. The VSELs are autologous and will not cause rejection and do not form tumors or cause other health risks. This is not a clinical trial but a focused patient based study intended to move forward the development of VSELs as a therapeutic for bone repair. It successful, these studies will provide the basis for the rapid clinical development of VSELs for craniofacial osseous regeneration and treatment of a number of other skeletal based disorders. PUBLIC HEALTH RELEVANCE: It is a goal of NeoStem to develop the therapeutic capabilities of Human VSELs to treat a host of diseases and disorders. Studies in this proposal are focused on establishing the utility of VSELs to repair bone and treat oral-craniofacial disorders. If the results of these studies in humans show safety and efficacy of adult autologous VSELs in bone repair, then we will attempt to further develop this cell therapy in clinical studies in the futureto establish the cells as a standard of care for the treatment of bone disease and loss.