A Biomarker for Predicting Responsiveness to Stem Cell Therapy Based on Mechanism-of-Action: Evidence from Cerebral Injury

• DOI: 10.1016/j.celrep.2020.107622
• Publication Date: 2020-05-12T14:44:28Z
• Authors: Richard E. Hartman; Neal H. Nathan; Nirmalya Ghosh; Cameron D. Pernia; Janessa Law; Ruslan Nuryyev; Amy Plaia; Alena Yusof; Beatriz Tone; Melissa Dulcich; Dustin R. Wakeman; Nejmi Dilmac; Walter D. Niles; Richard L. Sidman; Andre Obenaus; Evan Y. Snyder; Stephen Ashwal
• Keywords: Rats, Sprague-Dawley; Disease Models, Animal; 03 medical and health sciences; 0302 clinical medicine; Brain Injuries; Animals; Regenerative Medicine; Biomarkers; Rats; Stem Cell Transplantation; 3. Good health

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.