Characterization and Function of Histamine Receptors in Human Bone Marrow Stromal Cells

Abstract

There are several clinical trials worldwide utilizing BMSCs as a cellular therapy to modulate immune responses in patients suffering from various inflammatory conditions. A deeper understanding of the molecular mechanisms involved in this modulatory effect could help us design better, more effective protocols to treat immune mediated diseases. In our present study we demonstrated that human BMSCs express H1, H2 and H4 histamine receptors and they respond to histamine stimulation with an increased IL-6 production both in vitro and in vivo. Using different receptor antagonists we pinpointed the importance of the H1 histamine receptor, while Western blot analysis and application of various MAP kinase inhibitors highlighted the role of p38, ERK and JNK kinases in the observed effect. When BMSCs were pretreated with either histamine, or degranulated human mast cells they exhibited an enhanced IL-6 dependent anti-apoptotic effect on neutrophil granulocytes. Based on these observations it is likely that introduction of BMSCs into a histamine rich environment (such as any allergic setting) or pretreatment of these cells with synthetic histamine could have a significant modulatory effect on the therapeutic potential of BMSCs.

An MRI-Visible Non-Viral Vector Bearing GD2 Single Chain Antibody for Targeted Gene Delivery to Human Bone Marrow Mesenchymal Stem Cells

“…The purified pDNAs were resuspended in deionized water and kept in aliquots at a concentration of 2.4 µg/µL. hBMSCs isolation for research was approved by the institutional review board of the third affiliated hospital of Sun Yat-Sen University according to a protocol previously described [23]. The mouse anti-human GD2 monoclonal antibody (14.G2a), isotype antibody mouse IgG2a, and rabbit monoclonal antibody against EGFP were purchased from BD Bioscience Pharmingen (San Jose, CA, USA).…”

Bone marrow stromal cells as immunomodulators. A primer for dermatologists

“…In addition to EAE, a number of other studies have shed light on various molecular mechanisms of the immunosuppressive potential of BMSCs in animal models of diabetes 59–62 , arthritis 34,35 , lupus 36,37 , and colitis 35,38–41 . Clinical data indicate effective-ness in multiple sclerosis, systemic lupus erythematosus, and Crohn’s disease (Table 3.)…”

“…Based on their effect on B cell function 59–61 one can assume that pemphigus vulgaris and bullous pemphigoid could be affected by BMSC treatment. Finally, the regulation of mast cells by BMSCs 62 suggest that urticaria and mastocytosis might also serve as feasible targets for BMSC therapy.…”

“…As we mentioned, in an infectious setting BMSCs turn Ml monocytes/macrophages into an M2 phenotype, which are known to be more efficient in eliminating bacteria. BMSCs also support neutrophil functions, attracting these cells to the site of infection (by secreting IL-8) and prolonging their survival once they arrived (with the use of the anti-apoptotic IL-6) 62,63 . According to Krasnodembskaya et al BMSCs are also capable of secreting LL-37, an anti-microbial peptide 64 .…”

Impaired function of bone marrow stromal cells in systemic mastocytosis

“…These include the well-documented skeletal disease in patients with SM [4, 5], and abnormalities in the cellular composition of the BM including anemia [6]. As we have previously established that the human BMSCs bear all four histamine receptors [7], we wanted to examine if the increase in MCs might be associated with abnormalities of the BMSC compartment which might in turn impact disease pathology.…”