Abstract

BackgroundAdipose-derived mesenchymal stromal cells (ADSCs) are multipotent stromal cells. The cells secrete a number of cytokines and growth factors and show immunoregulatory and proangiogenic properties. Their properties may be used to repair damaged tissues. The aim of our work is to explain the muscle damage repair mechanism with the utilization of the human adipose-derived mesenchymal stromal cells (hADSCs).MethodsFor the hADSCs isolation, we used the subcutaneous adipose tissue collected during the surgery. The murine hind limb ischemia was used as a model. The unilateral femoral artery ligation was performed on 10–12-week-old male C57BL/6NCrl and NOD SCID mice. The mice received PBS− (controls) or 1 × 106 hADSCs. One, 3, 7, 14 and 21 days after the surgery, we collected the gastrocnemius muscles for the immunohistochemical analysis. The results were analyzed with relevant tests using the Statistica software.ResultsThe retention time of hADSCs in the limb lasted about 14 days. In the mice receiving hADSCs, the improvement in the functionality of the damaged limb occurred faster than in the control mice. More new blood vessels were formed in the limbs of the mice receiving hADSCs than in limbs of the control mice. hADSCs also increased the infiltration of the macrophages with the M2 phenotype (7-AAD−/CD45+/F4/80+/CD206+) into the ischemic limbs. hADSCs introduced into the limb of mice secreted interleukin-6. This cytokine stimulates the emergence of the proangiogenic M2 macrophages, involved, among others, in the repair of a damaged tissue. Both macrophage depletion and IL-6 blockage suppressed the therapeutic effect of hADSCs. In the mice treated with hADSCs and liposomes with clodronate (macrophages depletion), the number of capillaries formed was lower than in the mice treated with hADSCs alone. Administration of hADSCs to the mice that received siltuximab (human IL-6 blocker) did not cause an influx of the M2 macrophages, and the number of capillaries formed was at the level of the control group, as in contrast to the mice that received only the hADSCs.ConclusionsThe proposed mechanism for the repair of the damaged muscle using hADSCs is based on the activity of IL-6. In our opinion, the cytokine, secreted by the hADSCs, stimulates the M2 macrophages responsible for repairing damaged muscle and forming new blood vessels.

Highlights

  • Adipose-derived mesenchymal stromal cells (ADSCs) are multipotent stromal cells

  • The phenotype of human adipose-derived mesenchymal stromal cells (hADSCs) stabilized during cell culture The human hADSCs were isolated from subcutaneous adipose tissue from the abdominal region

  • The administration of hADSCs increases macrophages infiltration in the mouse model of hindlimb ischemia as compared to mMSC In the muscles, 3 days after the administration of hADSCs, we observed a significant increase in the area occupied by cells expressing F4/80 as compared to the control (PBS−) (4.29% of the area) and both murine Mesenchymal stromal cells (MSCs) groups: Mice adipose-derived mesenchymal stromal cells (mADSCs) (1.97% of the area) and mMB-MSCs (0.52% of the area)

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Summary

Introduction

Adipose-derived mesenchymal stromal cells (ADSCs) are multipotent stromal cells. The cells secrete a number of cytokines and growth factors and show immunoregulatory and proangiogenic properties. An increased number of blood vessels in the ischemic limb model was observed after the administration of mesenchymal stromal cells isolated from the adipose tissue (ADSC) [4]. ADSCs are multipotent stromal cells which secrete a number of cytokines and growth factors and show immunoregulatory and proangiogenic properties. A dominant cytokine secreted by ADSC is interleukin 6 (IL-6) [5], which is a pleiotropic cytokine This cytokine is involved in the immune response and influences the formation of new blood vessels by regulating the vascular endothelial growth factor (VEGF) [6]. M2 macrophages are involved in the inhibition of the inflammatory response, as in, they initiate the tissue repair processes They secrete and release many proangiogenic factors (chemokines, cytokines, growth factors) that stimulate endothelial cells to migrate and proliferate [9]

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