Electrophysiological Quality Control of Human Dopaminergic Neurons: Are We Doing Enough?

Abstract

The breakthrough of induced pluripotent stem (iPS) cell technology (Takahashi and Yamanaka, 2006) has allowed scientists to design protocols allowing the differentiation of these cells into the main cell types of our organism. This possibility is particularly exciting in the field of Parkinson's disease (PD), since early experiments using heterologous dopaminergic (DA) or chromaffin cells have demonstrated the ability of such cells, when injected in adequate sites, to improve symptoms of the disease in a sustained manner (Kefalopoulou et al., 2014). The possibility of reproducing this effect using autologous cells, thereby free of ethical concerns, is of course fascinating (Barker et al., 2017; Parmar et al., 2020). It has clearly been demonstrated that symptoms of experimental parkinsonism can be relieved in several species by such grafts (Kikuchi et al., 2017; Song et al., 2020), with a first human case report study yielding encouraging results (Schweitzer et al., 2020). Protocols are being refined to improve the yield of DA neurons and minimize the survival of undifferentiated cells (e.g., Piao et al., 2021). Immunohistochemical methods allow to clearly define the presence of DA neurons, the absence of other monoaminergic neurons (e.g., serotoninergic neurons) and the molecular subtype of these DA neurons (by examining the expression of a variety of transcription factors such as NURR1, PITX3, etc…). Many experiments have confirmed the possibility of obtaining preparations devoid of oncogenic potential. In the published papers, some efforts have been made to characterize the physiological properties of the DA neurons, but I argue that, in many cases, the data is not completely convincing and, more importantly, that the reader has no idea of the percentage of neurons that display the specific properties of these neurons. I believe that more standardization of these experiments is important to assess the functional quality of the future grafts. Although I reckon that safety is of paramount importance, I also believe that suboptimal functionality may impair the clinical effectiveness of future procedures.