Regeneration of peripheral nerves by transplanted sphere of human mesenchymal stem cells derived from embryonic stem cells.
In cell therapy, the most important factor for therapeutic efficacy is the stable supply of cells with best engraftment efficiency. To meet this requirement, we have developed a culture strategy such as three-dimensional sphere of human embryonic stem cell-derived mesenchymal stem cells (hESC-MSCs) in serum-free medium. To investigate the in vivo therapeutic efficacy of hESC-MSC spheres in nerve injury model, we transected the sciatic nerve in athymic nude mice and created a 2-mm gap. Transplantation of hESC-MSC as sphere repaired the injured nerve significantly better than transplantation of hESC-MSC as suspended single cells in regard to 1) nerve conduction (sphere; 28.81 ± 3.55 vs. single cells; 18.04 ± 2.10, p < 0.05) and 2) susceptibility of nerve stimulation at low voltage (sphere; 0.38 ± 0.08 vs. single cells; 0.66 ± 0.11, p < 0.05) at 8 weeks. Recovery after sphere transplantation was near-complete when compared with the data of normal control (sphere 28.81 ± 3.55 vs normal 32.62 ± 2.85 in nerve conduction : sphere 0.38 ± 0.08 vs normal 0.36 ± 0.67 in susceptibility of nerve stimulation, no significant difference, respectively). Recovery in function of the injured nerve was well corroborated by the histologic evidence of regenerated nerve. In the mechanistic analysis, the supernatant of sphere-forming hESC-MSC contains hepatocyte growth factor and insulin-like growth factor-binding protein-1 significantly more than the supernatant of the single cells of hESC-MSC has, which might be the key factors for the improved engraftment efficiency and greater regeneration of injured peripheral nerve.
National Research Laboratory for Stem Cell Niche and IRICT, Seoul National University Hospital, Seoul, Republic of Korea.
Eun Ju
EJ
Lee
Lianji
L
Xu
Gi-Hwan
GH
Kim
Soo Kyoung
SK
Kang
Sae-Won
SW
Lee
Sung-Hye
SH
Park
Sukwha
S
Kim
Tae Hyun
TH
Choi
Hyo-Soo
HS
Kim
D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D017690:Cell Transplantation / Q000379:methods*; D003094:Collagen / Q000737:chemistry; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004338:Drug Combinations; D053595:Embryonic Stem Cells / Q000166:cytology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism; D007797:Laminin / Q000737:chemistry; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009416:Nerve Regeneration / Q000502:physiology*; D010525:Peripheral Nerves / Q000473:pathology; D017933:Peripheral Nervous System; D011509:Proteoglycans / Q000737:chemistry; D012584:Sciatic Nerve / Q000502:physiology
D016895:Culture Media, Serum-Free; D004338:Drug Combinations; D018970:Insulin-Like Growth Factor Binding Protein 1; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D017228:Hepatocyte Growth Factor; D003094:Collagen