title: Reengineering autologous bone grafts with the stem cell activator WNT3A.
abstract: Autologous bone grafting represents the standard of care for treating bone defects but this biomaterial is unreliable in older patients. The efficacy of an autograft can be traced back to multipotent stem cells residing within the bone graft. Aging attenuates the viability and function of these stem cells, leading to inconsistent rates of bony union. We show that age-related changes in autograft efficacy are caused by a loss in endogenous Wnt signaling. Blocking this endogenous Wnt signal using Dkk1 abrogates autograft efficacy whereas providing a Wnt signal in the form of liposome-reconstituted WNT3A protein (L-WNT3A) restores bone forming potential to autografts from aged animals. The bioengineered autograft exhibits significantly better survival in the hosting site. Mesenchymal and skeletal stem cell populations in the autograft are activated by L-WNT3A and mitotic activity and osteogenic differentiation are significantly enhanced. In a spinal fusion model, aged autografts treated with L-WNT3A demonstrate superior bone forming capacity compared to the standard of care. Thus, a brief incubation in L-WNT3A reliably improves autologous bone grafting efficacy, which has the potential to significantly improve patient care in the elderly.
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Wei
authors: W
authors: Jing
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Andrew A
authors: AA
authors: Smith
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Bo
authors: B
authors: Liu
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Jingtao
authors: J
authors: Li
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Daniel J
authors: DJ
authors: Hunter
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Girija
authors: G
authors: Dhamdhere
authors: Dental School University Paris Descartes PRES Sorbonne Paris Cité, EA 2496, Montrouge, France; AP-HP Odontology Department Bretonneau, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France.
authors: Benjamin
authors: B
authors: Salmon
authors: UCLA Clinical and Translational Science Institute, Los Angeles, CA, USA.
authors: Jie
authors: J
authors: Jiang
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Du
authors: D
authors: Cheng
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Chelsey A
authors: CA
authors: Johnson
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Serafine
authors: S
authors: Chen
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Katherine
authors: K
authors: Lee
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Gurpreet
authors: G
authors: Singh
authors: Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA 94305, USA.
authors: Jill A
authors: JA
authors: Helms
mesh_terms: D000818:Animals; D016025:Bone Transplantation / Q000379:methods*; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D010012:Osteogenesis / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D013123:Spinal Fusion; D013234:Stem Cells / Q000166:cytology; D023822:Tissue Engineering / Q000379:methods; D060509:Wnt3A Protein / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: C501127:Dkk1 protein, mouse; C531384:Dkk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D008081:Liposomes; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D049452:Green Fluorescent Proteins
keywords: Age/ageing; Biomimetic material; Bone regeneration; Liposome; Osteogenesis; Spinal surgery