Human placenta-derived adherent cell treatment of experimental stroke promotes functional recovery after stroke in young adult and older rats.
BACKGROUND
Human Placenta-Derived Adherent Cells (PDAC®) are a novel mesenchymal-like cell population derived from normal human placental tissue. PDA-001 is a clinical formulation of PDAC® developed for intravenous administration. In this study, we investigated the efficacy of PDA-001 treatment in a rat model of transient middle cerebral artery occlusion (MCAo) in young adult (2-3 month old) and older rats (10-12 months old).


METHODS
To evaluate efficacy and determine the optimal number of transplanted cells, young adult Wistar rats were subjected to MCAo and treated 1 day post MCAo with 1×10(6), 4×10(6) or 8×10(6) PDA-001 cells (i.v.), vehicle or cell control. 4×10(6) or 8×10(6) PDA-001 cells were also tested in older rats after MCAo. Treatment response was evaluated using a battery of functional outcome tests, consisting of adhesive-removal test, modified Neurological Severity Score (mNSS) and foot-fault test. Young adult rats were sacrificed 56 days after MCAo, older rats were sacrificed 29 days after MCAo, and lesion volumes were measured using H&E. Immunohistochemical stainings for bromodeoxyuridine (BrdU) and von Willebrand Factor (vWF), and synaptophysin were performed.


RESULTS
In young adult rats, treatment with 4×10(6) PDA-001 cells significantly improved functional outcome after stroke (p<0.05). In older rats, significant functional improvement was observed with PDA-001 cell therapy in both of the 4×10(6) and 8×10(6) treatment groups. Functional benefits in young adult and older rats were associated with significant increases in the number of BrdU immunoreactive endothelial cells, vascular density and perimeter in the ischemic brain, as well as significantly increased synaptophysin expression in the ischemic border zone (p<0.05).


CONCLUSIONS
PDA-001 treatment significantly improved functional outcome after stroke in both young adult and older rats. The neurorestorative effects induced by PDA-001 treatment may be related to increased vascular density and synaptic plasticity.
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Amjad
A
Shehadah
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Jieli
J
Chen
Celgene Cellular Therapeutics, Warren, New Jersey, United States of America.
Ajai
A
Pal
Celgene Cellular Therapeutics, Warren, New Jersey, United States of America.
Shuyang
S
He
Celgene Cellular Therapeutics, Warren, New Jersey, United States of America.
Andrew
A
Zeitlin
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Xu
X
Cui
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Alex
A
Zacharek
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Yisheng
Y
Cui
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Cynthia
C
Roberts
Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, Michigan, United States of America.
Mei
M
Lu
Celgene Cellular Therapeutics, Warren, New Jersey, United States of America.
Robert
R
Hariri
Department of Neurology, Henry Ford Hospital, Detroit, Michigan, United States of America ; Department of Physics, Oakland University, Rochester, Michigan, United States of America.
Michael
M
Chopp
D000818:Animals; D001921:Brain / Q000503:physiopathology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology / Q000628:therapy; D008297:Male; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology*; D020521:Stroke / Q000503:physiopathology* / Q000628:therapy*