Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury.
We have investigated the potential of human pluripotent cells to restore function in rats paralyzed with a virus-induced motor neuronopathy. Cells derived from embryonic germ cells, termed embryoid body-derived (EBD) cells, introduced into the CSF were distributed extensively over the rostrocaudal length of the spinal cord and migrated into the spinal cord parenchyma in paralyzed, but not uninjured, animals. Some of the transplanted human cells expressed the neuroglial progenitor marker nestin, whereas others expressed immunohistochemical markers characteristic of astrocytes or mature neurons. Rare transplanted cells developed immunoreactivity to choline acetyltransferase (ChAT) and sent axons into the sciatic nerve as detected by retrograde labeling. Paralyzed animals transplanted with EBD cells partially recovered motor function 12 and 24 weeks after transplantation, whereas control animals remained paralyzed. Semi-quantitative analysis revealed that the efficiency of neuronal differentiation and extension of neurites could not account for the functional recovery. Rather, transplanted EBD cells protected host neurons from death and facilitated reafferentation of motor neuron cell bodies. In vitro, EBD cells secrete transforming growth factor-alpha (TGF-alpha) and brain-derived neurotrophic factor (BDNF). Neutralizing antibodies to TGF-alpha and to BDNF abrogated the ability of EBD-conditioned media to sustain motor neuron survival in culture, whereas neutralizing antibodies to BDNF eliminated the axonal outgrowth from spinal organotypics observed with direct coculture of EBD cells. We conclude that cells derived from human pluripotent stem cells have the capacity to restore neurologic function in animals with diffuse motor neuron disease via enhancement of host neuron survival and function.
Kerr
Douglas A
DA
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. dkerr@jhmi.edu
Lladó
Jerònia
J
Shamblott
Michael J
MJ
Maragakis
Nicholas J
NJ
Irani
David N
DN
Crawford
Thomas O
TO
Krishnan
Chitra
C
Dike
Sonny
S
Gearhart
John D
JD
Rothstein
Jeffrey D
JD
D018354:Alphavirus Infections / Q000150:complications / Q000821:virology; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002470:Cell Survival; D018792:Encephalitis, Viral / Q000150:complications / Q000821:virology; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D006085:Graft Survival; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D009043:Motor Activity; D016472:Motor Neuron Disease / Q000503:physiopathology / Q000628:therapy* / Q000821:virology; D009419:Nerve Tissue Proteins; D064231:Nestin; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D012845:Sindbis Virus / Q000472:pathogenicity; D033581:Stem Cell Transplantation; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D016211:Transforming Growth Factor alpha