Thérapie cellulaire pour le glaucome : régénération tissulaire grâce aux cellules souches mésenchymateuses
Stem cells have been presented as the key to regenerative medicine, where organ repair, cures for degenerative diseases and even the creation of new tissue could be achieved. Adult stem cells already possess a certain level of differentiation, which limits their potential effect to the organ where they were isolated. But one subtype, mesenchymal stem cells (MSC), possess a versatility which makes them ideal candidates for many treatments. It is commonly accepted that MSCs exert their effect through paracrine factors, but their precise mechanism of action remains uncertain.   As such factors could have a positive effect in many degenerative diseases, we wanted to study their regenerative potential in one of the most widespread ocular disease, open angle glaucoma. This disease is characterised by the destruction of retinal ganglion cells following a rise in intraocular pressure. This pressure rise is mostly caused by a dysfunction of the trabecular meshwork, the tissue regulating the outflow of aqueous humor from the eye.    Glaucoma progression can currently be controlled, but the disease cannot be cured. Meanwhile, trabecular regeneration could halt and even reverse disease progression. Thus, the objective of this thesis is to evaluate MSC potential in the regeneration of the trabecular meshwork and to understand any underlying mechanisms. To this end, we injected MSC or their secreted factors in a model of trabeculoplasty induced glaucoma.  We demonstrated that MSC can regenerate the damaged trabeculum and lower ocular pressure by reactivating progenitor cells located in the ciliary body. These cells proliferate and restore the trabeculum within one week after the initial treatment. We also demonstrated that MSC factors produced under hypoxic conditions induce progenitor cell activation. Such activation does not occur with MSC factors produced under normoxic conditions.   We have also observed that factors produced under hypoxic conditions are incapable of reactivating progenitor cells in an ex vivo setting. Thus, we wanted to verify if any other regenerative factors are produced in vivo after MSC injection. We have discovered that macrophages produce one such factor after their migration in the area of damage. Production of the macrophage factor requires contact with MSC paracrine factors. We have also observed that MSC regeneration was completely blocked following macrophage elimination from the organism. This positions macrophages as an essential intermediate in MSC-mediated tissue regeneration.   The results presented in this thesis represent an important step forward for the use of MSC in regenerative medicine.  They have established a basis for an open angle glaucoma treatment and added an important element for the comprehension of MSC regenerative mechanisms. This knowledge should have a significant impact for the treatment of ocular diseases and other illnesses in many different organs.
macrophages Mesenchymal stem cells Open angle glaucoma ocular regeneration trabeculum paracrine factors macrophages