In Vivo Transient and Partial Cell Reprogramming to Pluripotency as a Therapeutic Tool for Neurodegenerative Diseases

Abstract

In theory, human diseases in which a specific cell type degenerates, such as neurodegenerative diseases, can be therapeutically addressed by replacement of the lost cells. The classical strategy for cell replacement is exogenous cell transplantation, but now, cell replacement can also be achieved with in situ reprogramming. Indeed, many of these disorders are age-dependent, and "rejuvenating" strategies based on cell epigenetic modifications are a possible approach to counteract disease progression. In this context, transient and/or partial reprogramming of adult somatic cells towards pluripotency can be a promising tool for neuroregeneration. Temporary and controlled in vivo overexpression of Yamanaka reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc (OSKM)) has been proven feasible in different experimental settings and could be employed to facilitate in situ tissue regeneration; this regeneration can be accomplished either by producing novel stem/precursor cells, without the challenges posed by exogenous cell transplantation, or by changing the epigenetic adult cell signature to the signature of a younger cell. The risk of this procedure resides in the possible lack of perfect control of the process, carrying a potential oncogenic or unexpected cell phenotype hazard. Recent studies have suggested that these limits can be overcome by a tightly controlled cyclic regimen of short-term OSKM expression in vivo that prevents full reprogramming to the pluripotent state and avoids both tumorigenesis and the presence of unwanted undifferentiated cells. On the other hand, this strategy can enhance tissue regeneration for therapeutic purposes in aging-related neurological diseases as well. These data could open the path to further research on the therapeutic potential of in vivo reprogramming in regenerative medicine.

Reprogramming of Rat Fibroblasts into Induced Neurons by Small-Molecule Compounds In Vitro and In Vivo

“…Great advances have been made in in vitro cell replacement approaches for neurodegenerative diseases based on direct neural reprogramming. 65,66 Some scholars have directly reprogrammed mouse and human fibroblasts into neurons using specific neuronal TFs. 27,67 Many studies have confirmed that the combination of TFs such as Ascl1, Myt1, and Brn2 can successfully convert somatic cells into iNs.…”

“…In a previous study, fibroblasts were transformed into iPSCs as a cell source for cell replacement therapy. − However, the effects of exogenous TFs and instability of iPSCs raise concerns about the clinical safety of this strategy. Great advances have been made in in vitro cell replacement approaches for neurodegenerative diseases based on direct neural reprogramming. , Some scholars have directly reprogrammed mouse and human fibroblasts into neurons using specific neuronal TFs. , Many studies have confirmed that the combination of TFs such as Ascl1, Myt1, and Brn2 can successfully convert somatic cells into iNs . TFs such as Mash1 (Ascl1), Nurr1 (Nr4a2), and Lmx1a can directly reprogram mouse and human fibroblasts into functional dopaminergic neurons bypassing the iNSC stage .…”

MicroRNA‑29a promotes the neural differentiation of rat neural stem/progenitor cells by targeting KLF4

“…As a zinc finger-containing transcription factor, KLF4 has been found to be expressed in numerous types of mammalian cells, where it regulates diverse cellular processes, such as proliferation, differentiation and maintaining stemness (30)(31)(32). For example, in a previous study, following the transfection of the four genes, oct4, Sox2, KlF4 and c-Myc, somatic cells were reprogrammed and differentiated into induced pluripotent stem cells (33,34). The current study demonstrated that mir-29a downregulated the expression levels of KlF4, which were detected using rT-qPcr and western blotting.…”

Aging, Cellular Senescence, and Progressive Multiple Sclerosis

“…Immune-mediated physiological clearance of senescent cells could potentially be therapeutically enhanced by medications or vaccines aimed at priming the immune response to remove specific senescent populations (Burton and Stolzing, 2018 ; Song et al, 2020 ). Reprogramming of senescent cells may be another approach (Tamanini et al, 2018 ; Mahmoudi et al, 2019 ).…”