Cytoplasmic extracts from adipose tissue stromal cells alleviates secondary damage by modulating apoptosis and promotes functional recovery following spinal cord injury.
Spinal cord injury (SCI) typically results from sustained trauma to the spinal cord, resulting in loss of neurologic function at the level of the injury. However, activation of various physiological mechanisms secondary to the initial trauma including edema, inflammation, excito-toxicity, excessive cytokine release and apoptosis may exacerbate the injury and/or retard natural repair mechanisms. Herein, we demonstrate that cytoplasmic extracts prepared from adipose tissue stromal cells (ATSCs) inhibits H(2)O(2)-mediated apoptosis of cultured spinal cord-derived neural progenitor cells (NPCs) resulting in increased cell survival. The ATSC extracts mediated this effect by decreasing caspase-3 and c-Jun-NH2-terminal kinase (SAPK/JNK) activity, inhibiting cytochrome c release from mitochondria and reducing Bax expression levels in cells. Direct injection of ATSC extracts mixed with Matrigel into the spinal cord immediately after SCI also resulted in reduced apoptotic cell death, astrogliosis and hypo-myelination but did not reduce the extent of microglia infiltration. Moreover, animals injected with the ATSC extract showed significant functional improvement of hind limbs as measured by the BBB (Basso, Beattie and Bresnahan) scale. Collectively, these studies show a prominent therapeutic effect of ATSC cytoplasmic extracts on SCI principally caused by an inhibition of apoptosis-mediated cell death, which spares white matter, oligodendrocytes and neurons at the site of injury. The ability of ATSC extracts to prevent secondary pathological events and improve neurologic function after SCI suggests that extracts prepared from autologous cells harvested from SCI patients may have clinical utility.
Kang
Soo Kyung
SK
Department of Physiology, College of Medicine, Pusan National University, 1-10 Ami-Dong, Busan 602-739, South Korea. skkang@pusan.ac.kr
Yeo
Jee Eun
JE
Kang
Kyung Sun
KS
Phinney
Donald G
DG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002457:Cell Extracts / Q000627:therapeutic use*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects; D017154:Stromal Cells / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D002457:Cell Extracts; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3