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*Global* Cell Replacement Is Feasible Via Neural Stem Cell Transplantation: Evidence From The Dysmyelinated Shiverer Mouse Brain


Booma D. Yandava, Lori L. Billinghurst, and Evan Y. Snyder*
The National Academy of Sciences 0027-8424/99/967029-6
Vol. 96, Issue 12, 7029-7034, June 8, 1999

Harvard Medical School and Children's Hospital, Depts of Neurology,
Pediatrics, and NeuroSurgery,
Boston, MA 02115


Abstract

Many diseases of the Central Nervous System (CNS), particularly those of Genetic, Metabolic, or Infectious/Inflammatory Etiology, are characterized by "global" Neural Degeneration or Dysfunction.

Therapy might require widespread Neural Cell replacement, a challenge not regarded conventionally as amenable to Neural transplantation.

Mouse mutants characterized by CNS-wide White Matter Disease provide ideal models for testing the hypothesis that Neural Stem Cell transplantation might compensate for defective Neural Cell types in NeuroPathologies requiring cell replacement throughout the Brain.

The Oligodendrocytes of the Dysmyelinated Shiverer (shi) mouse are "globally" Dysfunctional because they lack Myelin Basic Protein (MBP) essential for effective Myelination. Therapy, therefore, requires widespread replacement with MBP-expressing Oligodendrocytes.

Clonal Neural Stem Cells transplanted at birth - using a simple IntraCerebroVentricular implantation technique - resulted in widespread engraftment throughout the shi Brain with repletion of MBP.

Accordingly, of the many donor cells that differentiated into Oligodendroglia - there appeared to be a shift in the fate of these multipotent cells toward an Oligodendroglial fate - a subgroup myelinated up to 52% (mean = approx 40%) of host Neuronal processes with better compacted Myelin of a thickness and periodicity more closely approximating normal.

A number of recipient animals evinced decrement in their symptomatic Tremor. Therefore, "global" neural cell replacement seems feasible for some CNS pathologies if cells with Stem-like features are used.


Communicated by: Richard L. Sidman,
Harvard Medical School, Southborough, MA,
April 6, 1999 (received for review February 23, 1999)

* To whom reprint requests should be addressed at:
Harvard Medical School,
Children's Hospital,
300 Longwood Avenue,
248 Enders Building,
Boston, MA 02115
e-mail: Snyder@A1.TCH.Harvard.Edu

Copyright 1999 by The National Academy of Sciences



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