Stem and Somatic Cell Monotherapy for the Treatment of Diabetic Foot Ulcers: Review of Clinical Studies and Mechanisms of Action.

Diabetic foot ulcer (DFU) is one of the most severe complications of diabetes mellitus, often resulting in a limb amputation. A cell-based therapy is a highly promising approach for an effective DFU treatment. However, there is no consensus regarding the most effective cell type for DFU treatment. Various cell types contribute to chronic wound healing via different mechanisms. For example, application of keratinocytes can stimulate migration of native keratinocytes from the wound edge, while mesenchymal stem cells can correct limb ischemia. To assess the effectiveness of a certain cell type, it should be administered as a monotherapy without other substances and procedures that have additional therapeutic effects. In the present review, we described therapeutic effects of various cells and provided an overview of clinical studies in which stem and somatic cell-based therapy was administered as a monotherapy. Topical application of somatic cells contributes to DFU healing only, while injection of mesenchymal stem cells and mononuclear cells can break a pathophysiological chain leading from insufficient blood supply to DFU development. At the same time, the systemic use of mesenchymal stem cells carries greater risks. Undoubtedly, cell therapy is a potent tool for the treatment of DFU. However, it is vital to conduct further high-quality clinical research to determine the most effective cell type, dosage and way of administration for DFU treatment. Ischemia, neuropathy and neuro-ischemia are underlying factors of diabetic foot ulcer. Stem and somatic cells monotherapy can improve chronic wound healing via different mechanisms.

Role of calcium ions in rapid effects of L-thyroxine on phosphoinositide metabolism in rat liver cells.

The role of calcium ions in the L-thyroxine-induced initiation of hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP2) and also the course of releasing individual fractions of inositol phosphates and diacylglycerides (DAG) were studied in liver cells during early stages of the hormone effect. L-Thyroxine stimulated a rapid hydrolysis in hepatocytes of PtdInsP2 labeled with [14C]linoleic acid and [3H]inositol mediated by phosphoinositide-specific phospholipase C. This was associated with accumulation of [14C]DAG, total inositol phosphates, [3H]inositol 1,4,5-trisphosphate (Ins1,4,5P3) and [3H]inositol 1,4-bisphosphate (Ins1,4P2). Elimination of calcium ions from the incubation medium of hepatocytes did not abolish the effect of thyroxine on the accumulation of [14C]DAG and total [3H]inositol phosphates. Preincubation of liver cells with TMB-8 increased the stimulatory effect of L-thyroxine on the accumulation of [14C]DAG. During the incubation of hepatocytes in the presence of the hormone the content of 14C-labeled fatty acids did not change. The L-thyroxine-induced accumulation of [3H]Ins1,4,5P3 and [3H]Ins1,4P2 did not depend on the presence of calcium ions in the incubation medium of the cells.

Thyroxine signal transduction in liver cells involves phospholipase C and phospholipase D activation. Genomic independent action of thyroid hormone.

BACKGROUND: Numerous investigations demonstrate a novel role of thyroid hormone as a modulator of signal transduction. Protein kinase C (PKC) is critical to the mechanism by which thyroid hormones potentiate both the antiviral and immunomodulatory actions of IFNgamma in different cells and regulate the exchange of signalling phospholipids in hepatocytes. Because nothing is known about accumulation of PKC modulator - diacylglycerol in cells treated with T4, we examined the nongenomic effect of thyroid hormones on DAG formation and phospholipase activation in liver cells. RESULTS: The results obtained provide the first demonstration of phospholipase C, phospholipase D and protein kinase C nongenomic activation and diacylglycerol (DAG) accumulation by L-T4 in liver cells. The experiments were performed in either the [14C]CH3COOH-labeled rat liver slices or isolated hepatocytes pre-labeled by [14C]oleic acid. L-T4 activates the DAG production in a concentration- and time-dependent manner. DAG formation in stimulated cells is biphasic and short-lived event: there is an initial, rapid rise in DAG concentration and then a slower accumulation that can be sustained for a few minutes. The early phase of L-T4 generated DAG only is accompanied by phosphatidylinositol 4,5-bisphosphate level decrease and inositol 1,4,5-trisphosphate formation while the second phase is abolished by PKC inhibitor l,(5-isoquinolinesulphonyl)2methylpiperasine dihydrochloride (H7) and propranolol. The second phase of DAG production is accompanied by free choline release, phosphatidylcholine content drop and phosphatidylethanol (Peth) formation. Inhibitor of phospholipase-C-dependent phosphoinositide hydrolysis, neomycin sulfate, reduced the Peth as well as the DAG response to L-T4. CONCLUSIONS: The present data have indicated the DAG signaling in thyroid hormone-stimulated liver cells. L-thyroxine activates a dual phospholipase pathway in a sequential and synchronized manner: phospholipase C initiates the DAG formation, and PKC mediates the integration of phospholipase D into the signaling response during the sustained phase of agonist stimulation.