A cutting-edge strategy for spinal cord injury treatment: resident cellular transdifferentiation

Spinal cord injuries (SCI) lead to the loss of motor and sensory functions due to irreversible neuronal loss. Current treatments are ineffective, and preclinical advances have not translated into clinical therapies. A promising regenerative strategy involves direct transformation of mature cells into functional neurons, known as transdifferentiation. This review analyzes the mechanisms of resident cellular transdifferentiation, discusses challenges, and provides new ideas for therapeutic approaches to SCI. Transdifferentiation, or direct reprogramming, is a process of transferring somatic cells from one lineage to another without an intermediate pluripotent state. This approach is faster, more efficient, and safer than iPSC-based therapies because it excludes the possibility of iPSC-related tumorigenesis. Transdifferentiation can occur in situ and is more suitable for in vivo tissue repair, mimicking cellular processes that occur with aging. This review summarizes the current state-of-the-art in transdifferentiation of human cells and resident cell transdifferentiation in the injury microenvironment in vivo. By dissecting and comparing the transdifferentiation mechanisms of different approaches, it aims to optimize transdifferentiation schemes. The search for appropriate transdifferentiation protocols in the direction of neuronal subtypes can effectively complement the specific functional neuronal subtypes of injuries.

• 1
  Neuronal transdifferentiation can be achieved mainly by ectopic overexpression of specific transcription factors (TFs). Key TFs like Ascl1, Brn2, and Myt1l can convert fibroblasts into functional neurons in vitro, which generate action potentials and form functional synapses. MicroRNAs (miRNAs) and small molecules, such as miR-9/9∗-124, can also induce neuronal transdifferentiation.
• 2
  In vivo transdifferentiation has shown that the central nervous system has more plasticity than previously thought. Overexpression of key TFs, such as SOX-2 and Ascl1, can transform glial cells into neurons in vivo. miRNA-mediated transdifferentiation also plays a role, with miRNAs like miR-302/367 promoting myelin regeneration in injured spinal cords.
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  Small molecules are non-immunogenic, not integrated into the genome, and their manipulation of intracellular targets is reversible. Small molecules like Forskolin, ISX9, CHIR99021, I-BET151, and Y-27632 (FICBY) can induce endogenous astrocytes into neurons in the mouse brain, showing the ability to connect to endogenous neurons.