Setting up stem cell therapy for human retina: from organotypic cultures to cell fusion understanding

Abstract

Visual impairments and different retinopathies have been silently increasing in the modern society and they become a medical hurdle in need to be addressed. Müller glial cells (MGCs), in lower vertebrates, show regenerative potential for the retina, however in the mammals this capacity is lost. However, it has been demonstrated in mice that fusion between MGCs and adult stem cells result in the formation of hybrids which detain some potential to regenerate the lost retinal neurons.

In the present work we hypothesize that also into the human retina cell fusion between adult stem cells and retinae resident MGCs can enhance a process resulting into retina rescue and regeneration. In this thesis we first demonstrated that cell fusion can occur between human MGCs (hMGCs) and adult stem cells in the human retinal organotypic cultures. We then isolated the hMGCs and we fused them with either hematopoietic stem cells or with human mesenchymal stem cells adipose-derived (hMSC AD) in culture. We found that the activation of the Wnt/b-catenin pathway can induce reprogramming of the hybrids, which, in turn, can then undergo differentiation and acquire some electrophysiological response. Finally, we set up a microinjection system to transplant the hybrids into human retinal organoids to finally study the hybrid differentiation in vivo.

With the strategy here exposed, we believe that it might represent the first step towards a potential regenerative therapy for human retinae via cell fusion and reprogramming. These observations might be the basis to develop an innovative approach to address in the long run the unmet medical need of the visual impairments.