TY - JOUR
T1 - Systemic DKK1 neutralization enhances human adipose-derived stem cell mediated bone repair
AU - Negri, Stefano
AU - Wang, Yiyun
AU - Sono, Takashi
AU - Qin, Qizhi
AU - Hsu, Ginny Ching Yun
AU - Cherief, Masnsen
AU - Xu, Jiajia
AU - Lee, Seungyong
AU - Tower, Robert J.
AU - Yu, Victoria
AU - Piplani, Abhi
AU - Meyers, Carolyn A.
AU - Broderick, Kristen
AU - Lee, Min
AU - James, Aaron W.
N1 - Publisher Copyright:
© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - Wnt signaling
KW - adipose stem cell
KW - adipose stromal cell
KW - bone healing
KW - bone repair
KW - bone tissue engineering
KW - mesenchymal stem cell
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U2 - 10.1002/sctm.20-0293
DO - 10.1002/sctm.20-0293
M3 - Article
C2 - 33377628
AN - SCOPUS:85098248955
SN - 2157-6564
VL - 10
SP - 610
EP - 622
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 4
ER -