Objectives: Genetic background determines frequency and differentiation potential of bone marrow stem cells of hematopoietic and mesenchymal compartments. The close anatomic proximity of the cells involved in the processes of skeletogenesis and early hematopoiesis in the bone marrow, and the peripheral immunosuppressive ability of osteoprogenitor cells indicate that cells of both common organ systems interact in controlling their function and might share common regulatory mechanisms. Also, mouse strains with defined mutations in gene products initially identified in lymphocytes have skeletal abnormalities. We, thus, explored the possibility that a correlation might exist between strainspecific differentiation or immunoregulatory potential of mesenchymal stem cells (MSC) and susceptibility to autoimmunity. Methods: We characterized MSC from NOD mice that spontaneously develop diabetes, DBA/1 in which collageninduced arthritis can be generated by injection of collagen type II in complete Freund’s adjuvant (CFA), C57Bl/10 mice susceptible to induction of experimental autoimmune uveitis following immunization with uveitogenic antigens emulsified in CFA and injection of pertussis toxin, and finally MSC from the Balb/c strain considered to be resistant to induction of autimmunity. We tested their in vitro clonogenic, differentiation, and growth potential, their immunophenotype by FACS analysis, their cytokine profile by ELISPOT analisys, and their immunomodulant activity by cell proliferation and blocking assays. Results: We found that the differentiation potential and the immunomodulant activity were distinct and not correlated properties within the same population of MSC. The ability to suppress lymphocyte proliferation was strain specific, being MSC from Balb/c mice the most effective in blocking lymphocyte proliferation, expressing the highest level of inhibitory molecules, and being able to strictly modulate cytokine expression. On the contrary, MSC from NOD mice did not show a very high antiproliferative activity, did not show basal expression of molecules involved in inhibitory pathways, and did not show a strict regulation of cytokine expression. MSC from C57Bl/10 mice showed an intermediated ability to suppress lymphocyte proliferation, to express inhibitory molecules, and regulate cytokine expression. Conclusions: Variations of the immunomodulant function of MSC might contribute to the strain-specific susceptibility to autoimmunity.
Immunomodulant activity of mesenchymal stem cells is strain-specific and correlates with susceptibility to autoimmunity
Negrini S;
2007-01-01
Abstract
Objectives: Genetic background determines frequency and differentiation potential of bone marrow stem cells of hematopoietic and mesenchymal compartments. The close anatomic proximity of the cells involved in the processes of skeletogenesis and early hematopoiesis in the bone marrow, and the peripheral immunosuppressive ability of osteoprogenitor cells indicate that cells of both common organ systems interact in controlling their function and might share common regulatory mechanisms. Also, mouse strains with defined mutations in gene products initially identified in lymphocytes have skeletal abnormalities. We, thus, explored the possibility that a correlation might exist between strainspecific differentiation or immunoregulatory potential of mesenchymal stem cells (MSC) and susceptibility to autoimmunity. Methods: We characterized MSC from NOD mice that spontaneously develop diabetes, DBA/1 in which collageninduced arthritis can be generated by injection of collagen type II in complete Freund’s adjuvant (CFA), C57Bl/10 mice susceptible to induction of experimental autoimmune uveitis following immunization with uveitogenic antigens emulsified in CFA and injection of pertussis toxin, and finally MSC from the Balb/c strain considered to be resistant to induction of autimmunity. We tested their in vitro clonogenic, differentiation, and growth potential, their immunophenotype by FACS analysis, their cytokine profile by ELISPOT analisys, and their immunomodulant activity by cell proliferation and blocking assays. Results: We found that the differentiation potential and the immunomodulant activity were distinct and not correlated properties within the same population of MSC. The ability to suppress lymphocyte proliferation was strain specific, being MSC from Balb/c mice the most effective in blocking lymphocyte proliferation, expressing the highest level of inhibitory molecules, and being able to strictly modulate cytokine expression. On the contrary, MSC from NOD mice did not show a very high antiproliferative activity, did not show basal expression of molecules involved in inhibitory pathways, and did not show a strict regulation of cytokine expression. MSC from C57Bl/10 mice showed an intermediated ability to suppress lymphocyte proliferation, to express inhibitory molecules, and regulate cytokine expression. Conclusions: Variations of the immunomodulant function of MSC might contribute to the strain-specific susceptibility to autoimmunity.
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