Reengineering autologous bone grafts with the stem cell activator WNT3A

Biomaterials. 2015 Apr;47:29-40. doi: 10.1016/j.biomaterials.2014.12.014. Epub 2015 Feb 2.

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.

Keywords: Age/ageing; Biomimetic material; Bone regeneration; Liposome; Osteogenesis; Spinal surgery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Transplantation / methods*
  • Bone and Bones / cytology
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Cell Differentiation
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Liposomes / chemistry
  • Mesenchymal Stem Cells / cytology
  • Mice
  • Osteogenesis / physiology*
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction
  • Spinal Fusion
  • Stem Cells / cytology
  • Tissue Engineering / methods
  • Wnt3A Protein / metabolism*
  • X-Ray Microtomography

Substances

  • Dkk1 protein, mouse
  • Dkk1 protein, rat
  • Intercellular Signaling Peptides and Proteins
  • Liposomes
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • Green Fluorescent Proteins