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.
Bone grafts are critically needed in surgical procedures to reconstruct skeletal defects resulting from trauma, chronic diseases, tumor removal and congenital anomalies. Autologous bone grafts are the clinical gold standard, but necessitate donor site trauma and morbidity;allogeneic or xenogeneic grafts are associated with immunorejection, pathogen transmission and suboptimal healing and synthetic materials such as hydroxyapatite suffer from poor integration. In this proposal, we have engineered vascularized bone grafts from the combined actions of vascular progenitor cells and bone progenitor cells;the vascularized bone grafts can be tailored to any shape and dimension, and integrate with host's existing bone, thus providing an improved treatment modality for bone defects.
|Jiang, Nan; Guo, Weihua; Chen, Mo et al. (2016) Periodontal Ligament and Alveolar Bone in Health and Adaptation: Tooth Movement. Front Oral Biol 18:1-8|
|Zheng, Y; Chen, M; He, L et al. (2015) Mesenchymal dental pulp cells attenuate dentin resorption in homeostasis. J Dent Res 94:821-7|
|Xiang, Lusai; Chen, Mo; He, Ling et al. (2014) Wnt5a regulates dental follicle stem/progenitor cells of the periodontium. Stem Cell Res Ther 5:135|
|Mendelson, Avital; Cheung, Yuk kee; Paluch, Kamila et al. (2013) Competitive stem cell recruitment by multiple cytotactic cues. Lab Chip 13:1156-64|
|Kim, Sahng G; Zheng, Ying; Zhou, Jian et al. (2013) Dentin and dental pulp regeneration by the patient's endogenous cells. Endod Topics 28:106-117|
|Bianco, Paolo; Cao, Xu; Frenette, Paul S et al. (2013) The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 19:35-42|
|Mao, Jeremy J; Kim, Sahng G; Zhou, Jian et al. (2012) Regenerative endodontics: barriers and strategies for clinical translation. Dent Clin North Am 56:639-49|
|Wang, X D; Kou, X X; Mao, J J et al. (2012) Sustained inflammation induces degeneration of the temporomandibular joint. J Dent Res 91:499-505|
|Nie, Hemin; Lee, Chang Hun; Tan, Jiali et al. (2012) Musculoskeletal tissue engineering by endogenous stem/progenitor cells. Cell Tissue Res 347:665-76|
|Kim, Sahng G; Zhou, Jian; Solomon, Charles et al. (2012) Effects of growth factors on dental stem/progenitor cells. Dent Clin North Am 56:563-75|
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