Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model
Muriel Sudres, Marie Maurer, Marieke Robinet, Jacky Bismuth, Frédérique Truffault, Diane Girard, Nadine Dragin, Mohamed Attia, Elie Fadel, Nicola Santelmo, Camille Sicsic, Talma Brenner, Sonia Berrih-Aknin
Muriel Sudres, Marie Maurer, Marieke Robinet, Jacky Bismuth, Frédérique Truffault, Diane Girard, Nadine Dragin, Mohamed Attia, Elie Fadel, Nicola Santelmo, Camille Sicsic, Talma Brenner, Sonia Berrih-Aknin
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Research Article Immunology

Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model

Abstract

Myasthenia gravis (MG) with anti–acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro–preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell–related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases.

Authors

Muriel Sudres, Marie Maurer, Marieke Robinet, Jacky Bismuth, Frédérique Truffault, Diane Girard, Nadine Dragin, Mohamed Attia, Elie Fadel, Nicola Santelmo, Camille Sicsic, Talma Brenner, Sonia Berrih-Aknin

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Figure 7

Mesenchymal stem cells (MSCs) inhibited human cell proliferation in the thymus and the spleen.

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Mesenchymal stem cells (MSCs) inhibited human cell proliferation in the ...
The proliferation status of human cells in the xenogeneic thymus (A) and the spleen (B) was analyzed at the mRNA level via real-time PCR. The values on the y axis (%MG 2–ΔCt) for the resting MSC (rMSC) and preconditioned MCS (cMSC) groups were normalized using the mean 2–ΔCt values of the MG group (levels set at 100%). Each symbol represents the 2–ΔCt value of 1 mouse, and the bars represent the mean values in the myasthenia gravis (MG) and cMSC groups. Four to 6 experiments are included (MG, n = 19 mice, rMSC, n = 15 and cMSC, n = 13 mice). P values were determined using the 1-way ANOVA test. *P < 0.05. (C–E) The proliferation status of human cells in the spleen was also analyzed at the protein level via IHC. (C) mki67 mRNA expression correlated with KI-67 fluorescence intensity. Each symbol represents 1 mouse, and 2 experiments are included: MG, black circles, n = 4; rMSC, dark gray squares, n = 3; cMSC, light gray triangles, n = 4; CTRL, open circles, n = 2. P values were determined using the linear regression test. (D and E) Upper panels, mosaic with nearly all spleen sections; lower panels, representative image showing human cells (lamin A/C–positive cells, in green) and proliferating cells (KI-67–positive cells, in red) among all splenocytes (DAPI positive cells, in blue) in the MG group (D) and the cMSC group (E). Scale bars: 200 μm (top panels) and 50 μm (bottom panels) in D and E.