Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: evidence from the effect of hypoxia-ischemia in the CNS on clonal "reporter" neural stem cells.
Clonal neural cells with stem-like features integrate appropriately into the developing and degenerating central and peripheral nervous system throughout the neuraxis. In response to hypoxic-ischemic (HI) injury, previously engrafted, integrated, and quiescent clonal neural stem cells (NSCs) transiently re-enter the cell cycle, migrate preferentially to the site of ischemia, and differentiate into neurons and oligodendrocytes, the neural cell types typically lost following HI brain injury. They also replenish the supply of immature uncommitted resident stem/progenitor cells. Although they yield astrocytes, scarring is inhibited. These responses appear to occur most robustly within a 3-7 day "window" following HI during which signals are elaborated that upregulate genetic programs within the NSC that mediate proliferation, migration, survival, and differentiation, most of which appear to be terminated once the "window closes" and the chronic phase ensues, sending the NSCs into a quiescent state. These insights derived from using the stem cell in a novel role--as a "reporter" cell--to both track and probe the activity of endogenous stem cells as well as to "interrogate" and "report" the genes differentially induced by the acutely vs. chronically injured milieu. NSCs may be capable of the replacement of cells, genes, and non-diffusible factors in both a widespread or more circumscribed manner (depending on the therapeutic demands of the clinical situation). They may be uniquely responsive to some types of neurodegenerative conditions. We submit that these various capabilities are simply the normal expression of the basic homeostasis-preserving biologic properties and attributes of a stem cell which, if used rationally and in concert with this biology, may be exploited for therapeutic ends.
Park
Kook In
KI
Department of Pediatrics and The Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea.
Hack
Michael A
MA
Ourednik
Jitka
J
Yandava
Booma
B
Flax
Jonathan D
JD
Stieg
Philip E
PE
Gullans
Stephen
S
Jensen
Francis E
FE
Sidman
Richard L
RL
Ourednik
Vaclav
V
Snyder
Evan Y
EY
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002999:Clone Cells; D007839:Functional Laterality; D020869:Gene Expression Profiling / Q000379:methods; D017930:Genes, Reporter / Q000502:physiology; D018816:Genes, cdc / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000503:physiopathology* / Q000601:surgery; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000502:physiology* / Q000648:ultrastructure; D013997:Time Factors
D001973:Bromodeoxyuridine