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Systemic DKK1 neutralization enhances human adipose-derived stem cell mediated bone repair
Stefano Negri1,2, Yiyun Wang1, Takashi Sono1
1Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Abstract:
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.
Insights
Targeting Dickkopf-1 (DKK1) with antibodies enhances bone repair by improving adipose-derived stem cell (ASC) survival and function. This approach shows promise for treating impaired bone healing, including osteoporosis.
Area of Science:
- Regenerative Medicine
- Stem Cell Biology
- Orthopedic Research
Background:
- Adipose-derived stem cells (ASCs) show potential for bone repair, but efficacy is inconsistent.
- Wnt signaling antagonists, like Dickkopf-1 (DKK1), can inhibit ASC function.
- DKK1 expression varies in human ASCs, potentially limiting their bone-healing capacity.
Purpose of the Study:
- To investigate the therapeutic potential of blocking DKK1 to enhance ASC-mediated bone regeneration.
- To evaluate the effect of anti-DKK1 antibodies on ASC osteogenic differentiation and in vivo bone repair.
Main Methods:
- Human ASCs were treated with anti-DKK1 antibodies in vitro.
- ASCs were engrafted into mouse femoral bone defects and treated systemically with anti-DKK1 or control.
- Bone repair, ASC engraftment, survival, and vascularization were assessed.
Main Results:
- Anti-DKK1 treatment increased in vitro osteogenic differentiation of ASCs via Wnt signaling.
- Systemic anti-DKK1 enhanced ASC engraftment, survival, and vascular ingrowth in vivo.
- Significant improvements in bone repair were observed in the anti-DKK1 treated group.
Conclusions:
- Neutralizing DKK1 with antibodies is a viable strategy to augment ASC-driven bone regeneration.
- This method holds promise for improving outcomes in challenging bone healing scenarios, such as osteoporotic fractures.
