Increasing Human Neural Stem Cell Transplantation Dose Alters Oligodendroglial and Neuronal Differentiation after Spinal Cord Injury

Katja M Piltti; Gabriella M Funes; Sabrina N Avakian; Ara A Salibian; Kevin I Huang; Krystal Carta; Noriko Kamei; Lisa A Flanagan; Edwin S Monuki; Nobuko Uchida; Brian J Cummings; Aileen J Anderson

doi:10.1016/j.stemcr.2017.04.009

Increasing Human Neural Stem Cell Transplantation Dose Alters Oligodendroglial and Neuronal Differentiation after Spinal Cord Injury

Stem Cell Reports. 2017 Jun 6;8(6):1534-1548. doi: 10.1016/j.stemcr.2017.04.009. Epub 2017 May 4.

Authors

Affiliations

¹ Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Physical & Medical Rehabilitation, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA. Electronic address: kpiltti@uci.edu.
² Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Anatomy & Neurobiology, University of California Irvine, Irvine, CA 92697, USA.
³ Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA.
⁴ Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Physical & Medical Rehabilitation, University of California Irvine, Irvine, CA 92697, USA.
⁵ Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Anatomy & Neurobiology, University of California Irvine, Irvine, CA 92697, USA; Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA; Department of Neurology, University of California Irvine, Irvine, CA 92697, USA.
⁶ Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92697, USA.
⁷ BOCO Silicon Valley, ReGen Med Division, Palo Alto, CA 94303, USA.
⁸ Sue & Bill Gross Stem Cell Center, University of California Irvine, Irvine, CA 92697, USA; Physical & Medical Rehabilitation, University of California Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments & Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Anatomy & Neurobiology, University of California Irvine, Irvine, CA 92697, USA.

Abstract

Multipotent human central nervous system-derived neural stem cells transplanted at doses ranging from 10,000 (low) to 500,000 (very high) cells differentiated predominantly into the oligodendroglial lineage. However, while the number of engrafted cells increased linearly in relationship to increasing dose, the proportion of oligodendrocytic cells declined. Increasing dose resulted in a plateau of engraftment, enhanced neuronal differentiation, and increased distal migration caudal to the transplantation sites. Dose had no effect on terminal sensory recovery or open-field locomotor scores. However, total human cell number and decreased oligodendroglial proportion were correlated with hindlimb girdle coupling errors. Conversely, greater oligodendroglial proportion was correlated with increased Ab step pattern, decreased swing speed, and increased paw intensity, consistent with improved recovery. These data suggest that transplant dose, and/or target niche parameters can regulate donor cell engraftment, differentiation/maturation, and lineage-specific migration profiles.

Keywords: cell dose; differentiation; fate; human neural stem cell; microenvironment; migration; spinal cord injury; stem cell niche dynamics; stem cell transplantation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, Nuclear / metabolism
Cell Differentiation*
Cell Lineage
Cell Movement
Cells, Cultured
Cellular Microenvironment
Gene Expression
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Microtubule-Associated Proteins / metabolism
Nerve Tissue Proteins / metabolism
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Neural Stem Cells / transplantation*
Neurons / cytology*
Neurons / metabolism
Oligodendrocyte Transcription Factor 2 / metabolism
Oligodendroglia / cytology*
Oligodendroglia / metabolism
Recovery of Function
Spinal Cord Injuries / therapy*
Stem Cell Niche

Substances

ARTN protein, human
Antigens, Nuclear
MAP2 protein, human
Microtubule-Associated Proteins
Nerve Tissue Proteins
OLIG2 protein, human
Oligodendrocyte Transcription Factor 2
neuronal nuclear antigen NeuN, human

Grants and funding

R01 NS049885/NS/NINDS NIH HHS/United States