Hyaluronic Acid Facilitates Angiogenesis of Endothelial Colony Forming Cell Combining With Mesenchymal Stem Cell via CD44/ MicroRNA-139-5p Pathway

Abstract

Stem cells and progenitor cells have been identified as potential new therapeutic options for severe limb ischemia to induce angiogenesis, and hyaluronic acid (HA) is commonly applied as a biomaterial in tissue engineering. However, the efficiency of HA combined with human umbilical cord blood-derived endothelial colony forming cells (ECFCs) and human umbilical-derived mesenchymal stem cells (MSCs) on angiogenesis is unclear. In the present study, we showed that HA promoted angiogenesis induced by MSCs-ECFCs in Matrigel plugs and promoted blood perfusion of murine ischemic muscles. Laser confocal microscopy revealed that human-derived cells grew into the host vasculature and formed connections, as shown by mouse-specific CD31+/human-specific CD31+ double staining. In vitro assays revealed that HA supported cell proliferation and migration, enhanced CD44 expression and reduced microRNA (miR)-139-5p expression. Further analysis revealed that miR-139-5p expression was negatively regulated by CD44 in ECFCs. Flow cytometry assays showed that HA increased CD31 positive cells proportion in MSC-ECFC and could be reversed by miR-139-5p mimics transfection. Moreover, the improvement of MSC-ECFC proliferation and migration induced by HA could be blocked by upregulation of miR-139-5p expression. In conclusion, HA facilitates angiogenesis of MSCs-ECFCs, and this positive effect be associated with activation of the CD44/miR-139-5p pathway, providing a promising strategy for improving severe limb ischemia.

Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway

“…Supporting our results, Luo et al [32] reported that in vitro assays showed that HA supports cell migration and proliferation. In their study, Moreno et al [33] concluded that the proliferation of BMSCs is stimulated by HA, which is non-toxic to the cells and actually induces an anti-inflammatory phenotype in BMSCs.…”

PFKFB3-mediated glycometabolism reprogramming modulates endothelial differentiation and angiogenic capacity of placenta-derived mesenchymal stem cells

“…Post-preparation, sections were stained with hematoxylin and eosin (H&E) for morphometric analysis. The blood vessels were stained with human-specific CD31 antibody (11,265–1-AP, Proteintech) and examined by microscope (Olympus, Lake Success, NY, USA) [ 37 ].…”

Antibodies against hyaluronan oligosaccharides in xenotransplantation

“…30 CD44-HA signaling is involved in development, angiogenesis, inflammation, T-cell recruitment and activation, tumor growth, and metastasis. 31,32 In an animal model of non-infectious lung injury using mice lacking CD44, HA fragments accumulate in the lung and exacerbate lung damage. 33 Thus, the inability to remove HA fragments results in significant inflammation and impaired clearance of apoptotic neutrophils.…”

“…This suggests that the longer the HA fragment is, the more binding sites to CD44 are present, reducing the probability of HA‐oligosaccharide dissociation from the cell surface 30 . CD44‐HA signaling is involved in development, angiogenesis, inflammation, T‐cell recruitment and activation, tumor growth, and metastasis 31,32 . In an animal model of non‐infectious lung injury using mice lacking CD44, HA fragments accumulate in the lung and exacerbate lung damage 33 .…”