The Journal of Experimental Medicine
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Published 5 April 2004. doi:10.1084/jem.20031385
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 937-945
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Regenerative Response in Ischemic Brain Restricted by p21cip1/waf1

Jianhua Qiu1, Yasushi Takagi1, Jun Harada1, Neil Rodrigues2, Michael A. Moskowitz1, David T. Scadden2, and Tao Cheng3

1 Neuroscience Center and Department of Radiology, 2 Center for Regenerative Medicine and Technology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129
3 University of Pittsburgh Cancer Institute and Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

Address correspondence to Tao Cheng, Office ste. 2.42e, Research Pavilion at The Hillman Cancer Center, 5117 Center Ave., Pittsburgh, PA 15213-1863. Phone: (412) 623-3249; Fax: (412) 623-7778; email: chengtao{at}pitt.edu

Neural precursor cells from adults have exceptional proliferative and differentiative capability in vitro yet respond minimally to in vivo brain injury due to constraining mechanisms that are poorly defined. We assessed whether cell cycle inhibitors that restrict stem cell populations in other tissues may participate in limiting neural stem cell reactivity in vivo. The cyclin-dependent kinase inhibitor, p21cip1/waf1 (p21), maintains hematopoietic stem cell quiescence, and we evaluated its role in the regenerative response of neural tissue after ischemic injury using the mice deficient in p21. Although steady-state conditions revealed no increase in primitive cell proliferation in p21-null mice, a significantly larger fraction of quiescent neural precursors was activated in the hippocampus and subventricular zone after brain ischemia. The hippocampal precursors migrated and differentiated into a higher number of neurons after injury. Therefore, p21 is an intrinsic suppressor to neural regeneration after brain injury and may serve as a common molecular regulator restricting proliferation among stem cell pools from distinct tissue types.

Key Words: neural stem cells • cell cycle • p21 • neural regeneration • brain ischemia

J. Qiu and Y. Takagi contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: BrdU, 5-bromodeoxyuridine; CKI, cyclin-dependent kinase inhibitor; CNS, central nervous system; DCX, doublecortin; EGF, epidermal growth factor; EIA, enzyme immunoassay; FGF, fibroblast growth factor; GCL, granule cell layer; HSC, hematopoietic stem cell; MCAO, middle cerebral artery occlusion; NPC, neural progenitor cell; NSC, neural stem cell; p21, p21cip1/waf1; PCNA, proliferating cell nuclear antigen; SGZ, subgranular zone; SVZ, subventricular zone; TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridinetriphosphate nick end labeling.


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