Go to the fake! Fudan Shanghai Doctor Peng Bo, Mao Ying's team, etc. proposed to verify the basic principles of endogenous nerve regeneration therapy

The research team found that the NeuroD1-mediated reprogramming of microglia-neurons reported by the Japanese team was not a real phenomenon, but an illusion caused by the imprecise design of the experiment

Recently, the Peng Bo Research Group of the Institute of Brain Science Transformation of Fudan University, the Mao Ying Research Group of Huashan Hospital Affiliated to Fudan University, and the Yuan Difei Research Group of Shanghai Mental Health Center systematically explored the Phenomenon of NeuroD1-mediated microglia-neuron reprogramming by means of live cell imaging, rigorous lineage tracing and pharmacology. On December 6, the results were published in Neuron, a top neuroscience journal.

Our brains are mainly made up of neurons and glial cells, both of which number about 1:1. Neurons perform the transmission and integration of neural signals, while glial cells play an important supportive and nutritive role. Unlike peripheral tissues and organs, neurons in the mammalian brain in adulthood are almost impossible to regenerate. As a result, in neurodegenerative lesions (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke, etc.), dead neurons cannot regenerate, resulting in irreversible and serious brain function damage. Unlike static neurons, glial cells have a certain ability to regenerate.

The researchers proposed that by manipulating a single gene, glial cells are induced to reprogram (also known as transdifferentiation) so that they differentiate into neurons. This idea can use a class of renewable cells (glial cells) to replace the lost non-renewable cells (neurons) to achieve endogenous nerve regeneration, thereby treating neurodegenerative lesions.

Microglia are the most regenerative glial cells in the brain. A previous study by Peng Bo's research group at Fudan University found that microglia can regenerate rapidly at an average rate of 20% per day. By inducing microglia to reprogram, it would be the equivalent of discovering an endless source of supplies that can be used to replenish damaged neurons in large quantities. Kinichi Nakashima's team from Japan reported in 2019 that NeuroD1 induces microglia to reprogram into neurons.

However, due to the limitations of research techniques, there is a lot of controversy within the field about whether the phenomenon is real. In addition, neuroscientists have recently debated other types of glial-neuron reprogramming.

Astonishing and significant conclusions must be rigorously verified. The joint research group proposed three basic principles for rigorous verification of endogenous nerve regenerative therapy:

1. Rigorous genealogical traceability proves its origin;

2. Explicit in vivo/live-cell imaging observed the transformation process of glial cells-neurons;

3. Remove this type of glial cell for reverse verification.

Based on these three basic principles, the research team systematically explored the Phenomenon of NeuroD1-mediated microglia-neuron reprogramming using a variety of means such as live-cell imaging, rigorous lineage tracing, and pharmacology. The team found that the NeuroD1-mediated reprogramming of microglia-neurons reported by the Japanese team was not a real phenomenon, but an illusion caused by a lack of rigorous experimental design.

This experimental illusion caused by non-specific leakage of the virus occurs more often in the relevant research field. In view of this, the most important aspect of this study is to propose three basic principles to verify/confirm the need for glial cell-neuron transdifferentiation, on the basis of which the phenomenon of endogenous nerve regeneration is de-false.

In addition, Peng Bo's research group of Fudan University has developed three protocols (Mr BMT, Mr PB and Mr MT) using the regenerative ability of microglia in the early stage, which for the first time realized the efficient exogenous transplantation/replacement of microglia at the whole brain scale. This regimen can be used to treat diseases caused by microglia mutations. However, one of the challenges of cell transplantation is how to prevent exogenous cells from getting out of control. Based on the fact that NeuroD1 can induce apoptosis in microglia, the research team proposed that in vitro modification, elements that induce the expression of NeuroD1 are placed in transplanted/replaced microglia. Once the transplanted/replaced microglia are out of control, microglia can be induced to apoptosis by switching this molecule, thereby improving the safety of microglia replacement/transplantation.

Dr. Rao Yanxia of Shanghai Mental Health Center is the first author and co-corresponding author of the paper. Professor Peng Bo of the Institute of Brain Science Transformation of Fudan University, Professor Mao Ying of Huashan Hospital Affiliated to Fudan University, and Professor Yuan Difei of Shanghai Mental Health Center are the co-corresponding authors of this article. The team contributed to this research by a number of people.

Author: Tang Wenjia

Editor: Tang Wenjia

Image source: Courtesy of the interviewee