TY - JOUR
T1 - Notch1 signaling determines the plasticity and function of fibroblasts in diabetic wounds
AU - Shao, Hongwei
AU - Li, Yan
AU - Pastar, Irena
AU - Xiao, Min
AU - Prokupets, Rochelle
AU - Liu, Sophia
AU - Yu, Kerstin
AU - Vazquez-Padron, Roberto I.
AU - Tomic-Canic, Marjana
AU - Velazquez, Omaida C.
AU - Liu, Zhao Jun
N1 - Funding Information:
We thank Dr Hallie J Quiroz for the critical editing of this manuscript. We also thank Dr F Radtke (Swiss Institute for Experimental Cancer Research) for providing us Notch1Loxp/LoxP mice and Dr Alice A Tomei (Department of Biomedical Engineering, University of Miami) for providing some NOD mice. This work was supported by grants from the National Institutes of Health (R01DK-071084, R01GM081570 to OC Velazquez, R01HL149452 to Z-J Liu and OC Velazquez, and R01NR015649, R01NR13881 to M Tomic-Canic).
Publisher Copyright:
© 2020 Shao et al.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/27
Y1 - 2020/10/27
N2 - Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin and non-diabetic wounds. Consistently, wound healing in the FSP-1+/2;ROSALSL-N1IC+/+ mouse, in which Notch1 is activated in fibroblasts, is delayed. Increased Notch1 activity in fibroblasts suppressed their growth, migration, and differentiation into myofibroblasts. Accordingly, significantly fewer myofibroblasts and less collagen were present in granulation tissues of the FSP-1+/2;ROSALSL-N1IC+/+ mice, demonstrating that high Notch1 activity inhibits fibroblast differentiation. High Notch1 activity in fibroblasts diminished their role in modulating the angiogenic response. We also identified that IL-6 is a functional Notch1 target and involved in regulating angiogenesis. These findings suggest that Notch1 signaling determines the plasticity and function of fibroblasts in wound healing and angiogenesis, unveiling intracellular Notch1 signaling in fibroblasts as potential target for therapeutic intervention in diabetic wound healing.
AB - Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin and non-diabetic wounds. Consistently, wound healing in the FSP-1+/2;ROSALSL-N1IC+/+ mouse, in which Notch1 is activated in fibroblasts, is delayed. Increased Notch1 activity in fibroblasts suppressed their growth, migration, and differentiation into myofibroblasts. Accordingly, significantly fewer myofibroblasts and less collagen were present in granulation tissues of the FSP-1+/2;ROSALSL-N1IC+/+ mice, demonstrating that high Notch1 activity inhibits fibroblast differentiation. High Notch1 activity in fibroblasts diminished their role in modulating the angiogenic response. We also identified that IL-6 is a functional Notch1 target and involved in regulating angiogenesis. These findings suggest that Notch1 signaling determines the plasticity and function of fibroblasts in wound healing and angiogenesis, unveiling intracellular Notch1 signaling in fibroblasts as potential target for therapeutic intervention in diabetic wound healing.
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U2 - 10.26508/LSA.202000769
DO - 10.26508/LSA.202000769
M3 - Article
C2 - 33109684
AN - SCOPUS:85094867303
VL - 3
JO - Life Science Alliance
JF - Life Science Alliance
SN - 2575-1077
IS - 12
ER -