Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

Abstract

BackgroundHuman dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as other MSCs. Hypoxia-preconditioning and hypoxia-inducible factor 1 (HIF-1) alpha overexpression significantly improves MSC therapeutics, but the mechanisms involved are not fully understood. In the present study, we characterize immunomodulatory properties of dental MSCs and determine changes in their ability to modulate adaptive and innate immune populations after HIF-1 alpha overexpression.MethodsHuman dental MSCs were stably transduced with green fluorescent protein (GFP-MSCs) or GFP-HIF-1 alpha lentivirus vectors (HIF-MSCs). A hypoxic-like metabolic profile was confirmed by mitochondrial and glycolysis stress test. Capacity of HIF-MSCs to modulate T-cell activation, dendritic cell differentiation, monocyte migration, and polarizations towards macrophages and natural killer (NK) cell lytic activity was assessed by a number of functional assays in co-cultures. The expression of relevant factors were determined by polymerase chain reaction (PCR) analysis and enzyme-linked immunosorbent assay (ELISA).ResultsWhile HIF-1 alpha overexpression did not modify the inhibition of T-cell activation by MSCs, HIF-MSCs impaired dendritic cell differentiation more efficiently. In addition, HIF-MSCs showed a tendency to induce higher attraction of monocytes, which differentiate into suppressor macrophages, and exhibited enhanced resistance to NK cell-mediated lysis, which supports the improved therapeutic capacity of HIF-MSCs. HIF-MSCs also displayed a pro-angiogenic profile characterized by increased expression of CXCL12/SDF1 and CCL5/RANTES and complete loss of CXCL10/IP10 transcription.ConclusionsImmunomodulation and expression of trophic factors by dental MSCs make them perfect candidates for cell therapy. Overexpression of HIF-1 alpha enhances these features and increases their resistance to allogenic NK cell lysis and, hence, their potential in vivo lifespan. Our results further support the use of HIF-1 alpha-expressing dental MSCs for cell therapy in tissue injury and immune disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0659-2) contains supplementary material, which is available to authorized users.

Glioma exosomes mediate the expansion and function of myeloid‐derived suppressor cells through microRNA‐29a/Hbp1 and microRNA‐92a/Prkar1a pathways

“…37 The overexpression of hypoxia-inducible factor 1 in MSCs inhibits the differentiation of DCs and strengthens the immunosuppressive function of CD14 + monocytes. 38 Thus, hypoxia might induce MDSC differentiation by modifying MSCs. In addition, according to Whiteside TL, MSCs that have been reprogramed by tumors deliver exosomes to immune cells, such as macrophages, in the TME and enhance their protumor functions.…”

O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells

“…In fact, stabilizing HIF1α through loss of the factor inhibiting HIF (FIH) or through the oxidative dimerization of the prolyl hydroxylase domain protein 2 (PHD2) facilitates metabolic adaptation to hypoxia 30,35 . Previous studies showed that HIF1αoverexpressed MSC exhibits high immunomodulatory effects and high resistance to hypoxia-induced apoptosis 36,37 . Taken together, the metabolic reprogramming of MSC by HIF1α regulation can be a promising strategy to improve MSC-based therapies.…”

Bone marrow-derived humoral factors suppress oxidative phosphorylation, upregulate TSG-6, and improve therapeutic effects on liver injury of mesenchymal stem cells

“…(23,24) HIF-1a has been further demonstrated to participate in various cell functions such as proliferation, angiogenesis, and immunoregulation, and is currently considered as one of the master regulators of the stemness. (25)(26)(27) Therefore, we have demonstrated the upregulation of HIF-1a upon culturing in BMC-CM under normoxic conditions. Intracellular upregulation of HIF-1a under hypoxia is generally considered to be primarily due to the oxygen-dependence of its degrading enzyme, but not from an increase in its production.…”