Partial reprogramming strategy for intervertebral disc rejuvenation by activating energy switch

Abstract

Rejuvenation of nucleus pulposus cells (NPCs) in degenerative discs can reverse intervertebral disc degeneration (IDD). Partial reprogramming is used to rejuvenate aging cells and ameliorate progression of aging tissue to avoiding formation of tumors by classical reprogramming. Understanding the effects and potential mechanisms of partial reprogramming in degenerative discs provides insights for development of new therapies for IDD treatment. The findings of the present study show that partial reprogramming through short‐term cyclic expression of Oct‐3/4, Sox2, Klf4, and c‐Myc (OSKM) inhibits progression of IDD, and significantly reduces senescence related phenotypes in aging NPCs. Mechanistically, short‐term induction of OSKM in aging NPCs activates energy metabolism as a “energy switch” by upregulating expression of Hexokinase 2 (HK2) ultimately promoting redistribution of cytoskeleton and restoring the aging state in aging NPCs. These findings indicate that partial reprogramming through short‐term induction of OSKM has high therapeutic potential in the treatment of IDD.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan

“…As aging and age-associated diseases are a major societal burden, the need for aging interventions such as cellular reprogramming has grown (Mahmoudi, Xu and Brunet, 2019; Garmany, Yamada and Terzic, 2021). Although multiple groups have now demonstrated that in vivo partial reprogramming via transient application of OSKM can rejuvenate molecular hallmarks of aging, restore tissue function, and extend lifespan in mouse models, the risks of oncogenesis and inefficient gene delivery hinders clinical development (Ocampo et al ., 2016; Kurita et al ., 2018; de Lázaro et al ., 2019; Lu et al ., 2020; Rodríguez-Matellán et al ., 2020; Sarkar et al ., 2020; Chen et al ., 2021; Cheng et al ., 2022; Hishida et al ., 2022). Interestingly, a more translational approach for the induction of cellular reprogramming based on the use of small molecules has been recently developed (Hou et al ., 2013; Zhao et al ., 2015; Cao et al ., 2018; Guan et al ., 2022).…”

“…Importantly, this limited cyclic expression of OSKM was sufficient to ameliorate multiple aging hallmarks and extend the lifespan of a progeroid mouse strain (Ocampo et al ., 2016). Improved regenerative capacity and function has also been demonstrated following therapeutic application of cellular reprogramming in multiple tissues and organs including the intervertebral disc, heart, skin, skeletal muscle, liver, optic nerve, and dentate gyrus (Ocampo et al ., 2016; Kurita et al ., 2018; de Lázaro et al ., 2019; Lu et al ., 2020; Rodríguez-Matellán et al ., 2020; Chen et al ., 2021; Cheng et al ., 2022; Hishida et al ., 2022). Furthermore, several groups have demonstrated the ability to restore multiple aging phenotypes and reset the epigenetic clock utilizing translational non-integrative methods such as modified mRNAs encoding for six transcription factors (OSKM + Lin28 and Nanog) or adeno-associated virus for expression of three factors (OSK) (Sarkar et al ., 2020; Lu et al ., 2020).…”

Thermosensitive hydrogel‐based GPR124 delivery strategy for rebuilding blood‐spinal cord barrier

“…And detection was carried out per 5 min before and after sequentially adding with oligomycin, carbonyl cyanide 4‐(trifluoromethoxy)phenylhydrazone (FCCP) and rotenone/antimycin A (Agilent, China). Wave software and Graphpad were employed to process and analyze the data obtained 25 …”

The occurrence and development of induced pluripotent stem cells

“…It is currently unclear whether p53 knockout can be safely applied in clinical practice, and selecting specific mediators to target the p53 pathway may be a future research direction. In addition, Cheng et al, 2022 reported that reprogramming of degenerative intervertebral disc nucleus pulposus cells (NPCs) can reverse intervertebral disc degeneration (IDD) through short-term OSKM induction.…”