Engineering of Vascularized Bone

项目摘要 骨移植是骨科手术修复骨缺损的关键。 创伤、慢性病、肿瘤切除和先天畸形。骨组织工程提供 在改变骨骼重建的临床实践方面具有巨大的潜力。然而，有几个 关键障碍制约了骨组织工程向临床的转化。 重要的是，骨组织工程的关键障碍之一不是骨本身；相反，它是 不理想的血运重建。来自我们和其他人的新兴工作已经开始探索一种令人兴奋的 两个不同的干细胞/祖细胞群体之间的相互作用，这些干细胞/祖细胞产生骨骼和 血管生成，即间充质干细胞(MSCs)和造血干细胞(HSCs)。 造血干细胞和骨髓间充质干细胞联合移植的生物工程血管生成与目前的研究进展 血管生成途径包括生长因子传递或构建血管类似物。在……里面 在发育过程中，HSCs和MSCs协同作用诱导(血管化)成骨。在 成年后，MSCs与HSCs共同生活在作为焦点的其他基质细胞的骨髓壁龛中 关于加强学习的问题。MSCs通常被分离为贴壁细胞(用于组织培养 聚苯乙烯)被骨组织工程界使用，而非贴壁的造血干细胞通常 被丢弃了。我们的初步数据，如最近发表在《公共科学图书馆·综合》上的一份报告所述，表明联合- 移植的MSC和HSC细胞系产生了带血管的异位骨，比 移植MSC或单独移植HSC。这些发现，以及最近对MSC-HSC的发现 其他人的相互影响，激发了我们的核心假设，即共同移植MSCs和HSCs 在原位模型中再生带血管的骨。头盖骨的缺陷代表了广泛的 利用模型进行骨愈合和巨大的临床挑战。目前的骨替代物，如 羟基磷灰石和移植物低于外科医生的预期。因此，这一行动的总体目标是 建议通过HSCs和HSCs的协同作用在体内原位工程血管化的骨 MSCs。尽管HSCs和MSCs的联合移植在骨组织中是一个新的概念 工程学，我们认为需要理解大量的基础生物学，其中一些 在将这一方法转换到临床环境之前，这是本提案中计划的。一个 作为我们的长期目标，我们将探索令人兴奋的潜力，即可以分离MSCs和HSCs 在单个门诊患者的骨髓抽吸过程中，并最小限度地进行处理以再生 依赖血管的组织，如骨、脂肪、神经和真皮移植物。

Project Summary Bone grafts are critically needed in the surgical reconstruction of skeletal defects resulting from trauma, chronic diseases, tumor removal and congenital anomalies. Bone tissue engineering offers tremendous potential in transforming the clinical practice of skeletal reconstruction. However, several critical barriers have restricted the translation of bone tissue engineering into clinical practice. Importantly, one of the key barriers in bone tissue engineering is not bone per se; instead, it is suboptimal vascularization. Emerging work from us and others has begun to explore an exciting cross-talk between two distinctive populations of stem/progenitor cells that generate bone and angiogenesis, namely mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs). Bioengineered angiogenesis by co-transplantation of HSCs and MSCs is a departure from current angiogenesis approaches including growth factor delivery or fabricating blood vessel analogs. In development, HSCs and MSCs function synergistically to induce (vascularized) osteogenesis. In the adult, MSCs co-reside with HSCs in bone marrow niches among other stromal cells that are the focus on intensifying studies. MSCs are conventionally isolated as adherent cells (to tissue culture polystyrene) by bone tissue engineering community, whereas non-adherent HSCs are conventionally discarded. Our preliminary data, as documented in a recent report in PloS One, demonstrate that co- transplantation of MSC and HSC lineages yielded vascularized ectopic bone, more significantly than the transplantation of MSC or HSC alone. These findings, and also recent discoveries of MSC-HSC cross-talk by others, have motivated our central hypothesis that co-transplanted MSCs and HSCs regenerate vascularized bone in an orthotopic model. The calvarial defect represents a widely utilized model for bone healing and substantial clinical challenges. Current bone substitutes such as hydroxyapatite and grafts are below the surgeon's expectations. Accordingly, the overall goal of this proposal is to engineer vascularized bone in vivo orthotopically from synergistic actions of HSCs and MSCs. Although co-transplantation of HSCs and MSCs represents a novel concept in bone tissue engineering, we believe that a great deal of fundamental biology needs to be understood, some of which are planned in this proposal, prior to the translation of this approach to clinical setting. An exciting potential that will be explored as our long-term goal is that MSCs and HSCs can be isolated in a single outpatient bone marrow aspiration procedure, and minimally manipulated to regenerate vasculature-dependent tissues such as bone, adipose, nerve and dermal grafts.