A Biomarker for Predicting Responsiveness to Stem Cell Therapy Based on Mechanism-of-Action: Evidence from Cerebral Injury.
To date, no stem cell therapy has been directed to specific recipients-and, conversely, withheld from others-based on a clinical or molecular profile congruent with that cell's therapeutic mechanism-of-action (MOA) for that condition. We address this challenge preclinically with a prototypical scenario: human neural stem cells (hNSCs) against perinatal/neonatal cerebral hypoxic-ischemic injury (HII). We demonstrate that a clinically translatable magnetic resonance imaging (MRI) algorithm, hierarchical region splitting, provides a rigorous, expeditious, prospective, noninvasive "biomarker" for identifying subjects with lesions bearing a molecular profile indicative of responsiveness to hNSCs' neuroprotective MOA. Implanted hNSCs improve lesional, motor, and/or cognitive outcomes only when there is an MRI-measurable penumbra that can be forestalled from evolving into necrotic core; the core never improves. Unlike the core, a penumbra is characterized by a molecular profile associated with salvageability. Hence, only lesions characterized by penumbral > core volumes should be treated with cells, making such measurements arguably a regenerative medicine selection biomarker.
['Hartman|Richard E|RE|', 'Nathan|Neal H|NH|', 'Ghosh|Nirmalya|N|', 'Pernia|Cameron D|CD|', 'Law|Janessa|J|', 'Nuryyev|Ruslan|R|', 'Plaia|Amy|A|', 'Yusof|Alena|A|', 'Tone|Beatriz|B|', 'Dulcich|Melissa|M|', 'Wakeman|Dustin R|DR|', 'Dilmac|Nejmi|N|', 'Niles|Walter D|WD|', 'Sidman|Richard L|RL|', 'Obenaus|Andre|A|', 'Snyder|Evan Y|EY|', 'Ashwal|Stephen|S|']
D000818:Animals D015415:Biomarkers D001930:Brain Injuries D004195:Disease Models, Animal D051381:Rats D017207:Rats, Sprague-Dawley D044968:Regenerative Medicine D033581:Stem Cell Transplantation
hypoxic-ischemic injury MRI neuroprotection penumbra regenerative medicine cerebral palsy patient stratification recovery-of-function stroke transplantation