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 - Funding Information:
A.W.J. was supported by the NIH/NIAMS (R01 AR070773, K08 AR068316), NIH/NIDCR (R21 DE027922), Department of Defense (W81XWH‐18‐1‐0121, W81XWH‐18‐1‐0336, W81XWH‐18‐10613), American Cancer Society (Research Scholar Grant RSG‐18‐027‐01‐CSM), the Maryland Stem Cell Research Foundation, and the Musculoskeletal Transplant Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health or Department of Defense. We thank the JHU microscopy facility for their technical assistance.
Funding Information:
A.W.J. was supported by the NIH/NIAMS (R01 AR070773, K08 AR068316), NIH/NIDCR (R21 DE027922), Department of Defense (W81XWH-18-1-0121, W81XWH-18-1-0336, W81XWH-18-10613), American Cancer Society (Research Scholar Grant RSG-18-027-01-CSM), the Maryland Stem Cell Research Foundation, and the Musculoskeletal Transplant Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Department of Defense. We thank the JHU microscopy facility for their technical assistance.
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 -