Neonatal-Inspired Reprogramming of Microglial Pan-Programmed Cell Death Enhances Regeneration in Adult Spinal Cord Injury

Beibei Yu; Yongfeng Zhang; Yujie Yang; Shijie Yang; Haining Wu; Xue Gao; Yiming Hao; Shengyou Li; Bing Xia; Jintao Liu; Lingli Guo; Borui Xue; Mingze Qin; Huangtao Chen; Jianzhong Li; Shouping Gong; Teng Ma; Jinghui Huang

doi:10.34133/research.0759

Neonatal-Inspired Reprogramming of Microglial Pan-Programmed Cell Death Enhances Regeneration in Adult Spinal Cord Injury

Research (Wash D C). 2025 Jul 2:8:0759. doi: 10.34133/research.0759. eCollection 2025.

Authors

Beibei Yu^{1

2}, Yongfeng Zhang^{1

2}, Yujie Yang¹, Shijie Yang^{1

2}, Haining Wu¹, Xue Gao¹, Yiming Hao¹, Shengyou Li¹, Bing Xia¹, Jintao Liu^{1

3}, Lingli Guo¹, Borui Xue¹, Mingze Qin¹, Huangtao Chen², Jianzhong Li⁴, Shouping Gong^{2

5}, Teng Ma^{1

6}, Jinghui Huang¹

Affiliations

¹ Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
² Department of Neurosurgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, China.
³ Department of Orthopedics, Naval Hospital of Eastern Theater, Zhoushan 316000, China.
⁴ Department of Thoracic Surgery, Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
⁵ Xi'an Medical University, Xi'an, China.
⁶ Military Medical Innovation Center, Fourth Military Medical University, Xi'an 710032, China.

Abstract

In adult mammals, programmed cell death (PCD) facilitates tissue remodeling and regeneration in spinal cord injury (SCI), but excessive activation impedes SCI repair. However, no comprehensive pan-PCD atlas exists that encompasses diverse cell death patterns to fully elucidate PCD in adult SCI and develop strategies for modulating the excessive PCD response. Here, we identified neonatal mice with balanced PCD post-SCI as an ideal model for adult SCI. Accordingly, we developed "Thanatoset", an SCI-specific gene panel to map tissue and cellular pan-PCD dynamics across neonatal and adult mice. Microglia were identified as pivotal mediators of pan-PCD, showing greater vulnerability in adults than in neonates. According to computational drug screening, withaferin A can revert microglial pan-PCD in adults to a neonatal-like regenerative state. Histological, functional, and molecular analyses corroborated that withaferin A enhances SCI recovery in adults by modulating microglial pan-PCD. These findings highlight the therapeutic potential of the pan-PCD framework for developing strategies to restore regeneration and improve SCI outcomes.