The Contribution of Endogenous and Exogenous Stem Cells in Fracture Repair

Throughout the lifespan, bone remodels in response to damage, such as fracture. However, diseases such as osteoporosis can cause impaired bone healing, increasing the risk of progression to non-repairing defects called fracture non-unions. Promoting the healing of fracture non-unions is a promising target for bone tissue engineering due to the limited success of current clinical treatment methods. There has been significant research on the use of stem cells with and without biomaterial scaffolds to treat bone fractures due to their promising regenerative capabilities. However, the relative roles of transplanted stem cells (exogenous stem cells) and stem cells found naturally in the body (endogenous stem cells) and their overall contribution to in vivo fracture repair is not well understood, thereby delaying the translation of new tissue engineering therapies to the clinic. The purpose of this research was to determine the interaction between exogenous and endogenous stem cells and biomaterials during bone fracture healing. This study was conducted using a burr-hole fracture model in a mesenchymal stem cell lineaging-tracing mouse. Burr-hole fractures were treated with collagen-I biomaterial loaded with and without green fluorescent protein tagged induced pluripotent stem cells. Using lineage-tracing, the roles of exogenous and endogenous stem cells during bone fracture repair could be elucidated. It was determined that in both a normal and impaired model of fracture healing treatment with exogenous stem cells did not result in improved bone formation and did not promote the recruitment of endogenous stem cells. However, treatment with exogenous stem cells in an impaired model of healing may offer healing advantages compared to in a normal model of healing. The outcomes of this study provide fundamental knowledge required for developing more effective stem cell and biomaterial therapies to treat bone fractures.

Year	Entry
2001	Homminga J, Huiskes R, Van Rietbergen B, Rüegsegger P, Weinans H. Introduction and evaluation of a gray-value voxel conversion technique. J Biomech. April 2001;34(4):513-517.
2007	Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA. January 24, 2007;297(4):387-394.
2005	Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. December 2005;115(12):3318-3325.
2010	Boskey AL, Coleman R. Aging and bone. J Dent Res. December 2010;89(2):1333-1348.
2011	Zimmermann EA, Schaible E, Bale H, Barth HD, Tang SY, Reichert P, Busse B, Alliston T, Ager JW III, Ritchie RO. Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales. Proc Natl Acad Sci USA. August 30, 2011;108(35):14416-14421.
2009	Colnot C. Skeletal cell fate decisions within periosteum and bone marrow during bone regeneration. J Bone Miner Res. February 2009;24(2):274-282.
2014	Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKEy Rep. January 2014;3:481.
2014	Damaraju S. The Role of Cell Communication and 3d Cell-Matrix Environment in a Stem Cell-Based Tissue Engineering Strategy for Bone Repair [PhD thesis]. Calgary, AB: University of Calgary; July 2014.
2014	Zhou BO, Yue R, Murphy MM, Peyer JG, Morrison SJ. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. August 7, 2014;15(2):154-168.
2003	Lee K, Jessop H, Suswillo R, Zaman G, Lanyon L. Bone adaptation requires oestrogen receptor-α. Nature. July 24, 2003;424(6947):389.
1996	van Rietbergen B, Odgaard A, Kabel J, Huiskes R. Direct mechanics assessment of elastic symmetries and properties of trabecular bone architecture. J Biomech. December 1996;29(12):1653-1657.
2002	Logan M, Martin JF, Nagy A, Lobe C, Olson EN, Tabin CJ. Expression of Cre recombinase in the developing mouse limb bud driven by a Prxl enhancer. genesis. June 2002;33(2):77-80.
2004	Kaneko TS, Bell JS, Pejcic MR, Tehranzadeh J, Keyak JH. Mechanical properties, density and quantitative CT scan data of trabecular bone with and without metastases. J Biomech. April 2004;37(4):523-530.
1984	Currey JD. Effects of differences in mineralization on the mechanical properties of bone. Philos Trans R Soc Lond B Biol Sci. February 13, 1984;304(1121):509-518.
2014	Taiani JT, Buie HR, Campbell GM, Manske SL, Krawetz RJ, Rancourt DE, Boyd SK, Matyas JR. Embryonic stem cell therapy improves bone quality in a model of impaired fracture healing in the mouse; tracked temporally using in vivo micro-CT. Bone. July 2014;64:263-272.
2013	Taiani JT, Krawetz RJ, Yamashita A, Pauchard Y, Buie HR, Ponjevic D, Boyd SK, Rancourt DE, Matyas JR. Embryonic stem cells incorporate into newly formed bone and do not form tumors in an immunocompetent mouse fracture model. Cell Transplant. 2013;22(8):1453-1462.
2009	Robling AG, Turner CH. Mechanical signaling for bone modeling and remodeling. Crit Rev Eukaryot Gene Expr. 2009;19(4):319-338.
2008	Shapiro F. Bone development and its relation to fracture repair: the role of mesenchymal osteoblasts and surface osteoblasts. Eur Cell Mater. 2008;15:53-76.
2006	Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, Gerig G. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. NeuroImage. July 1, 2006;31(3):1116-1128.
2009	Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. February 4, 2009;301(5):513-521.
2006	Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat Genet. December 2006;38(12):1424-1429.
2006	Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. December 2006;17(12):1726-1733.
1994	Frost HM. Wolff's law and bone's structural adaptations to mechanical usage: an overview for clinicians. Angle Orthod. June 1994;64(3):175-188.

Year

Entry

2001

Homminga J, Huiskes R, Van Rietbergen B, Rüegsegger P, Weinans H. Introduction and evaluation of a gray-value voxel conversion technique. J Biomech. April 2001;34(4):513-517.

2007

Center JR, Bliuc D, Nguyen TV, Eisman JA. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA. January 24, 2007;297(4):387-394.

2005

Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. December 2005;115(12):3318-3325.

2010

Boskey AL, Coleman R. Aging and bone. J Dent Res. December 2010;89(2):1333-1348.

2011

Zimmermann EA, Schaible E, Bale H, Barth HD, Tang SY, Reichert P, Busse B, Alliston T, Ager JW III, Ritchie RO. Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales. Proc Natl Acad Sci USA. August 30, 2011;108(35):14416-14421.