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Research progress in immunomodulatory properties of mesenchymal stem cells (III)

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3.2 The immunoregulatory effect of mesenchymal stem cells on B cells

B cells are pluripotent stem cells derived from bone marrow. With the stimulation of antigens and T cells, they proliferate in large quantities and further differentiate and develop into plasma cells capable of secreting antibodies. Mesenchymal stem cells have a certain inhibitory effect on the proliferation and differentiation of B cells. Mesenchymal stem cells can induce B cell proliferation and differentiation through cell contact. These conclusions may be related to the cell purification method, culture environment and detection time point, etc., and further research is needed. In addition, the functions of B cells secreting antibodies and expressing chemokine receptors CXCR4, CXCR5, and CCR7 are inhibited by mesenchymal stem cells, while the secretion of B cell costimulatory molecules and cytokines is not affected by mesenchymal stem cells.

The effect of mesenchymal stem cells on B cells is achieved through cell contact, and PD-1 / PDL-1 pathway is an important way for mesenchymal stem cells to inhibit B cells. Studies have shown that PD-1 can dephosphorylate some key signal transducers of BCR signaling by accumulating phosphatase, thereby hindering BCR signaling and inhibiting B cell activation. In addition, there are studies suggesting that T cells play an important role in the immune regulation of mesenchymal stem cells to B cells. Mesenchymal stem cells inhibit the proliferation and differentiation of B cells, but require the interaction between T cells and mesenchymal stem cells.

In addition to the key role of cell contact, mesenchymal stem cells regulate B cell function. Soluble cytokines also play a role that cannot be ignored. The study found that mesenchymal stem cells secrete CCL2, and achieve immune regulation of B cells by suppressing transcriptional activator protein 3 and inducing the production of paired box protein 5 (PAX5). In the mesenchymal stem cell co-culture system, the m RNA expression of Blimp-1 is significantly reduced, and the m RNA expression of PAX-5 is increased. Inhibiting the expression of Blimp-1 and promoting the expression of PAX-5 can inhibit the proliferation and differentiation of B cells.

3.3 The immunomodulatory effect of mesenchymal stem cells on NK cells

NK cells are short for natural killer cells. It is different from T cells and B cells; it does not require specific antibodies to participate in the killing of target cells or antigen-specific sensitization. The main role of NK cells in the innate immunity of the human body is to distinguish normal and abnormal cells by recognizing the ligands of corresponding activated receptors and inhibitory receptors on target cells. They also play a role in immune surveillance.

Mesenchymal stem cells can inhibit the proliferation and function of NK cells. NK cells are stimulated by activated cytokines, resulting in high expression of NK cell surface activated receptors NKp30, NKG2D, NKp44, CD69. The activated receptors on the surface of these cells are closely related to the function of NK cells. When NK cells and mesenchymal stem cells are co-cultured, the expressions of NK cell activation receptors NKp30 and NKG2D will be reduced, and NKp44 will not be expressed. Therefore, mesenchymal stem cells inhibit the cytotoxicity of NK cells by inhibiting the expression of NK cell activation receptors.

FN-γ plays a key role in the inhibition of mesenchymal stem cells on NK cells. The sensitivity of mesenchymal stem cells to NK cytotoxicity can be reduced by the presence of IFN-γ. The role of IFN-γ may be to induce mesenchymal stem cells to overexpress HLA molecules and interact with the inhibitory receptors of NK cells, thereby inhibiting the cytotoxicity of NK cells. Indoleamine 2,3-dioxygenase, prostaglandin E2, HLA-G play a major role in the inhibition of mesenchymal stem cells on NK cells. The HLA-G receptor is expressed on the surface of a leukocyte called LILRB, and can be expressed on the surface of T, B, and NK cells. The interaction of HLA-G / LILRB2 blocks the MEK / ERK signaling pathway and inhibits the cytotoxicity of NK cells. Adding indoleamine 2,3-dioxygenase or prostaglandin E2 to the mixed culture of mesenchymal stem cells and NK cells can restore the proliferation of NK cells to a certain extent. In the presence of IFN-γ and tumor necrosis factor alpha, mesenchymal stem cells interact with NK cells, mesenchymal stem cells secrete prostaglandin E2, and subsequently prostaglandin E2 can promote indoleamine 2,3-dioxygenase synthesis. In addition, the inhibitory effect of mesenchymal stem cells on NK cells is concentration-dependent. As the ratio of NK / mesenchymal stem cells increases, the inhibitory effect of mesenchymal stem cells on NK cells weakens.

3.4 The immunomodulatory effect of mesenchymal stem cells on dendritic cells

Dendritic cells are important antigen-presenting cells, derived from pluripotent hematopoietic stem cells. Immature dendritic cells have extremely strong antigen uptake, processing and processing capabilities. After ingesting the antigen or being stimulated, immature dendritic cells (CD14-, CD1a +) can differentiate into mature dendritic cells (CD80 +, CD83 +, CD86 +), and during this process, their antigen uptake and processing capacity will be significantly reduced, and their ability to present antigens and stimulate immune responses will be enhanced. Dendritic cells are presented to the corresponding CD8 + T cells and CD4 + T cells through the abundant antigen peptide-MHC class Ⅰ molecular complex and antigen peptide-MHC class Ⅱ molecular complex on their membrane surface, thereby activating T cell response and allowing T cells provide costimulatory molecules to fully activate T cells.

Mesenchymal stem cells can inhibit the differentiation of pluripotent hematopoietic stem cells into dendritic cells and the maturation of dendritic cells. Under the stimulation of granulocyte-macrophage stimulating factor / interleukin 4, the co-culture of mesenchymal stem cells and monocytes reduced the expression of CD1a and the high expression of CD14, indicating that the differentiation of dendritic cells was inhibited. In addition, under the stimulation of lipopolysaccharide, mesenchymal stem cells were co-cultured with dendritic cells, the expression of maturation marker CD83 of dendritic cells was decreased, the expression of costimulatory molecules CD80 and CD86 on the surface of dendritic cells was decreased, and the expression of costimulatory molecules CD80 and CD86 on the surface of DR was decreased, the expression of antigen presentation molecule HLA-DR was decreased, and the secretion of interleukin 2 was decreased, indicating that mesenchymal stem cells inhibited the maturation of dendritic cell. When the ratio of mesenchymal stem cells / monocytes is high (1:10), the inhibitory effect of mesenchymal stem cells on the differentiation of monocytes into dendritic cells can be completely achieved by soluble factors. When the ratio of mesenchymal stem cells / monocytes is low (1:20 or 1:40), mesenchymal stem cells exert their inhibitory effect mainly through cell contact. Mesenchymal stem cells can inhibit the differentiation of CD34 + -derived CD14 + precursor cells and monocytes into CD1a + dendritic cells, and inhibit the maturation and function of dendritic cells. The addition of macrophage colony stimulating factor and interleukin 6 antibody can reduce the expression of CD14, but cannot restore the expression of CD1a, suggesting that macrophage colony stimulating factor and interleukin 6 are involved in the suppression of mesenchymal stem cells.

The inhibitory effect of mesenchymal stem cells on the differentiation and maturation of dendritic cells indirectly leads to the inhibition of T cell activation, thereby suppressing the adaptive immune response. Mesenchymal stem cells have an inhibitory effect on dendritic cells through cell contact and soluble factors. This inhibitory effect may also involve macrophage colony stimulating factor, interleukin 6 and prostaglandin E2, and its specific mechanism needs further study.

At present, there are many clinical trials on the immune regulation of mesenchymal stem cells, and different mesenchymal stem cell isolation methods and different mesenchymal stem cell sources have different effects on the immune regulation of mesenchymal stem cells. Mesenchymal stem cells play an immunoregulatory role in the microenvironment, and different microenvironments also have different effects on their immune regulation.

References

[1] Che N, Li X, Zhang L, et al. Impaired B cell inhibition by lupus bone marrow mesenchymal stem cells is caused by reduced CCL2 expression. J Immunol.2014;193(10):5306-5314.

[2] Ribeiro A, Laranjeira P, Mendes S, et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Res Ther.2013;4(5):125.

[3] Nekanti U, Dastidar S, Venugopal P, et al. Increased proliferation and analysis of differential gene expression in human Wharton's jelly-derived mesenchymal stromal cells under hypoxia[J]. International Journal of Biological Sciences, 2010, 6 (5) :499-512.

[4] Boxall SA, Jones E. Markers for characterization of bone marrow multipotential stromal cells[J]. Stem Cells International, 2012, 2012, 975871.


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