Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 10, Issue 4, Pages 610-622Publisher
OXFORD UNIV PRESS
DOI: 10.1002/sctm.20-0293
Keywords
adipose stem cell; adipose stromal cell; bone healing; bone repair; bone tissue engineering; mesenchymal stem cell; Wnt signaling
Categories
Funding
- NIH/NIAMS [R01AR070773, K08AR068316]
- NIH/NIDCR [R21 DE027922]
- Department of Defense [W81XWH-18-1-0121, W81XWH-18-1-0336, W81XWH-18-10613]
- American Cancer Society [RSG-18-027-01-CSM]
- Maryland Stem Cell Research Foundation
- Musculoskeletal Transplant Foundation
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Research has shown that anti-DKK1 neutralizing antibodies can enhance the osteogenic differentiation of human adipose-derived stem cells, aiding in bone repair, and demonstrating potential beneficial effects in a mouse model.
Progenitor cells from adipose tissue are able to induce bone repair; however, inconsistent or unreliable efficacy has been reported across preclinical and clinical studies. Soluble inhibitory factors, such as the secreted Wnt signaling antagonists Dickkopf-1 (DKK1), are expressed to variable degrees in human adipose-derived stem cells (ASCs), and may represent a targetable molecular brake on ASC mediated bone repair. Here, anti-DKK1 neutralizing antibodies were observed to increase the osteogenic differentiation of human ASCs in vitro, accompanied by increased canonical Wnt signaling. Human ASCs were next engrafted into a femoral segmental bone defect in NOD-Scid mice, with animals subsequently treated with systemic anti-DKK1 or isotype control during the repair process. Human ASCs alone induced significant but modest bone repair. However, systemic anti-DKK1 induced an increase in human ASC engraftment and survival, an increase in vascular ingrowth, and ultimately improved bone repair outcomes. In summary, anti-DKK1 can be used as a method to augment cell-mediated bone regeneration, and could be particularly valuable in the contexts of impaired bone healing such as osteoporotic bone repair.
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