Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Orthopaedic and Trauma Surgery Unit, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, Verona, Italy.
Stem Cells Transl Med. 2021 Apr;10(4):610-622. doi: 10.1002/sctm.20-0293. Epub 2020 Dec 30.
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.
脂肪组织中的祖细胞能够诱导骨修复；然而，临床前和临床研究报告的疗效不一致或不可靠。可溶性抑制因子，如分泌的 Wnt 信号拮抗剂 Dickkopf-1（DKK1），在人脂肪来源干细胞（ASCs）中的表达程度不同，可能代表着 ASC 介导的骨修复的可靶向“分子刹车”。在这里，观察到抗 DKK1 中和抗体增加了人 ASC 的体外成骨分化，伴随着经典 Wnt 信号的增加。随后，将人 ASC 移植到 NOD-Scid 小鼠的股骨节段性骨缺损中，在修复过程中用系统抗 DKK1 或同种型对照处理动物。单独的人 ASC 诱导了显著但适度的骨修复。然而，系统抗 DKK1 诱导了人 ASC 植入和存活的增加、血管侵入的增加，并最终改善了骨修复结果。总之，抗 DKK1 可用作增强细胞介导的骨再生的方法，在骨愈合受损的情况下特别有价值，例如骨质疏松性骨修复。
