Deficiency of liver-derived insulin-like growth factor-I (IGF-I) does not interfere with the skin wound healing rate.

Ileana Ruxandra Botusan,Sergiu-Bogdan Catrina,Kerstin Brismar,Ishrath Ansurudeen,John-Olov Jansson,Jacob Grünler,Sampath Narayanan,Xiaowei Zheng,Christopher Illies,Freja S Calissendorff,Johan Svensson,Vivekananda Gupta Sunkari,Claes Ohlsson,Andrzej T Slominski

doi:10.1371/journal.pone.0193084

Ileana Ruxandra Botusan, Sergiu-Bogdan Catrina + Show 12 more

Open Access

https://doi.org/10.1371/journal.pone.0193084

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Abstract

ObjectiveIGF-I is a growth factor, which is expressed in virtually all tissues. The circulating IGF-I is however derived mainly from the liver. IGF-I promotes wound healing and its levels are decreased in wounds with low regenerative potential such as diabetic wounds. However, the contribution of circulating IGF-I to wound healing is unknown.Here we investigated the role of systemic IGF-I on wound healing rate in mice with deficiency of liver-derived IGF-I (LI-IGF-I-/- mice) during normal (normoglycemic) and impaired wound healing (diabetes).MethodsLI-IGF-I-/- mice with complete inactivation of the IGF-I gene in the hepatocytes were generated using the Cre/loxP recombination system. This resulted in a 75% reduction of circulating IGF-I. Diabetes was induced with streptozocin in both LI-IGF-I-/- and control mice. Wounds were made on the dorsum of the mice, and the wound healing rate and histology were evaluated. Serum IGF-I and GH were measured by RIA and ELISA respectively. The expression of IGF-I, IGF-II and the IGF-I receptor in the skin were evaluated by qRT-PCR. The local IGF-I protein expression in different cell types of the wounds during wound healing process was analyzed using immunohistochemistry.ResultsThe wound healing rate was similar in LI-IGF-I-/- mice to that in controls. Diabetes significantly delayed the wound healing rate in both LI-IGF-I-/- and control mice. However, no significant difference was observed between diabetic animals with normal or reduced hepatic IGF-I production. The gene expression of IGF-I, IGF-II and IGF-I receptor in skin was not different between any group of animals tested. Local IGF-I levels in the wounds were similar between of LI-IGF-I-/- and WT mice although a transient reduction of IGF-I expression in leukocytes in the wounds of LI-IGF-I-/- was observed seven days post wounding.ConclusionDeficiency in the liver-derived IGF-I does not affect wound healing in mice, neither in normoglycemic conditions nor in diabetes.

Highlights

IGF-I has growth promoting effects and it is expressed in virtually all tissues [1]
The wound healing rate was similar in LI-IGF-I-/- mice to that in controls
Inactivation of IGF-I gene in the liver of LI-IGF-I-/-mice resulted in a 75% reduction of serum IGF-I (Fig 1A)

Summary

Introduction

IGF-I has growth promoting effects and it is expressed in virtually all tissues [1]. The longitudinal body growth was considered to be dependent on the IGF-I produced in the liver under the control of growth hormone (GH) [2]. This theory was challenged by the finding that mice lacking the liver IGF-I secretion have unaffected postnatal body growth [3,4,5]. A local secretion of IGF-I was demonstrated in multiple tissues [6]. IGF-I promotes wound healing by multiple mechanisms as it has chemotactic activity for endothelial cells, it stimulates the proliferation of keratinocytes and fibroblasts, and it increases the wound strength [8]

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