Downregulation of thymosin beta4 in neural progenitor grafts promotes spinal cord regeneration.
Thymosin beta4 (Tbeta4) is an actin-binding peptide whose expression in developing brain correlates with migration and neurite extension of neurons. Here, we studied the effects of the downregulation of Tbeta4 expression on growth and differentiation of murine neural progenitor cells (NPCs), using an antisense lentiviral vector. In differentiation-promoting medium, we found twice the number of neurons derived from the Tbeta4-antisense-transduced NPCs, which showed enhanced neurite outgrowth accompanied by increased expression of the adhesion complex N-cadherin-beta-catenin and increased ERK activation. Importantly, when the Tbeta4-antisense-transduced NPCs were transplanted in vivo into a mouse model of spinal cord injury, they promoted a significantly greater functional recovery. Locomotory recovery correlated with increased expression of the regeneration-promoting cell adhesion molecule L1 by the grafted Tbeta4-antisense-transduced NPCs. This resulted in an increased number of regenerating axons and in sprouting of serotonergic fibers surrounding and contacting the Tbeta4-antisense-transduced NPCs grafted into the lesion site. In conclusion, our data identify a new role for Tbeta4 in neuronal differentiation of NPCs by regulating fate determination and process outgrowth. Moreover, NPCs with reduced Tbeta4 levels generate an L1-enriched environment in the lesioned spinal cord that favors growth and sprouting of spared host axons and enhances the endogenous tissue-repair processes.
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
Cristiana
C
Mollinari
Lucia
L
Ricci-Vitiani
Massimo
M
Pieri
Corrado
C
Lucantoni
Anna Maria
AM
Rinaldi
Mauro
M
Racaniello
Ruggero
R
De Maria
Cristina
C
Zona
Roberto
R
Pallini
Daniela
D
Merlo
Enrico
E
Garaci
D000818:Animals; D001369:Axons / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002450:Cell Communication; D016373:DNA, Antisense; D004195:Disease Models, Animal; D015536:Down-Regulation; D051379:Mice; D009416:Nerve Regeneration / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000628:therapy; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D013687:Telencephalon / Q000166:cytology; D013947:Thymosin / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D000099201:Thymosin beta(4)
D015820:Cadherins; D016373:DNA, Antisense; D039842:Neural Cell Adhesion Molecule L1; D013947:Thymosin; D051176:beta Catenin; D000099201:Thymosin beta(4)