中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (10): 1699-1700.doi: 10.4103/1673-5374.255620

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

人神经干细胞移植解决与创伤性脑损伤相关的多种病理问题

  

  • 出版日期:2019-10-15 发布日期:2019-10-15

Human neural stem cell transplants to address multiple pathologies associated with traumatic brain injury

Helene Clervius, Mirza Baig, Anil Mahavadi, Shyam Gajavelli   

  1. University of Miami Miller School of Medicine, Miami, FL, USA
  • Online:2019-10-15 Published:2019-10-15
  • Contact: Shyam Gajavelli, PhD, sgajavel@miami.edu.

摘要:

orcid: 0000-0002-5947-6973 (Shyam Gajavelli)

Abstract:

Traumatic brain injury (TBI), an unmet need: TBI is an alteration in brain function caused by an external force with evidence of brain pathology. It could be from a bump, blow, blast or jolt to the head including penetrating the cranium. TBI is a public health concern worldwide due to its economic impact. Most TBIs are survivable, do not need hospitalization but may influence productivity. A smaller percentage of TBI due to falls or penetrating TBI (PTBI) needs hospitalization and accounts for largest fraction of TBI care costs. PTBI especially that involving firearm injury is an increasingly serious issue. In the United States, PTBI is an issue both in the military and civilian context costing more than $70–75 billion annually. PTBI has become increasingly survivable including previously lethal midline crossing of projectile due to brain trauma foundation guidelines as well as timely neurosurgical intervention. The extent of recovery is proportional to initial damage; injuries limited to single hemisphere stabilize earlier than those crossing the midline do. However, currently the consequence of surviving a PTBI is most likely to be permanent disability. Rate of disability has not changed over the past 5 decades. Almost 3.2 million Americans live with neurobehavioral disability i.e., chronic cognitive and functional impairment requiring support from their families and the State, with lifetime costs of millions of dollars per patient. The TBI lesion is dynamic with continued brain atrophy, which correlates with persistent neurological deficit and overall social outcome. Observations of post-TBI tissue loss by pathologists were confirmed by longitudinal imaging studies in living TBI survivors. Progressive volume loss was coincident with persistent neuroinflammation thought to be due to chronic microglial activation. In a study of veterans living with TBI spanning4 decades, loss of tissue following PTBI was approximately 56 mL. Magnification of the primary injury via secondary mechanism underlies such volume loss and consequent disability. The PTBI penumbra (tissue surrounding the PTBI injury core) is render vulnerable by pyroptosis of chronically activated microglia. Continued pyroptosis of microglia and adjacent cells facilitate the lesion expansion into otherwise intact remote regions. Spontaneous recovery in TBI generally takes place within the first 3 months after injury and is mainly due to neural plasticity but not endogenous reparative neurogenesis. Success in restoring an injured brain with current therapies is limited by inability of central nervous system to regenerate spontaneously. Hence, current medical treatments albeit unsuccessfully, have sought to (i) prevent neuroinflammation driven deterioration and (ii) replace lost cells. The historical failure of acute neuroprotective trials has led to alternate approachesi.e., recruit endogenous neural stem cells (NSCs) or replace via transplantation of exogenous NSCs with a goal to rebuild circuitry. Both preclinical and clinical attempts to boost endogenous NSCs have failed to repair injured brains. In addition, the concept of recruiting endogenous NSCs to repair injured brain developed in rodents may have limited scope in humans given the differences in neurogenesis rate and recruitment distances. Could precise stereotactic placement of NSCs help address the unmet need and repair an injured brain?