Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration.
Hematopoietic stem cell (HSC) proliferation is tightly regulated by a poorly understood complex of positive and negative cell-cycle regulatory mechanisms. Necdin (Ndn) is an evolutionally conserved multifunctional protein that has been implicated in cell-cycle regulation of neuronal cells. Here, we provide evidence that necdin plays an important role in restricting excessive HSC proliferation during hematopoietic regeneration. We identify Ndn as being preferentially expressed in the HSC population on the basis of gene expression profiling and demonstrate that mice deficient in Ndn show accelerated recovery of the hematopoietic system after myelosuppressive injury, whereas no overt abnormality is seen in steady-state hematopoiesis. In parallel, after myelosuppression, Ndn-deficient mice exhibit an enhanced number of proliferating HSCs. Based on these findings, we propose that necdin functions in a negative feedback loop that prevents excessive proliferation of HSCs during hematopoietic regeneration. These data suggest that the inhibition of necdin after clinical myelosuppressive treatment (eg, chemotherapy, HSC transplantation) may provide therapeutic benefits by accelerating hematologic recovery.
Kubota
Yasushi
Y
Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan. kubotay@cdb.riken.jp
Osawa
Masatake
M
Jakt
Lars Martin
LM
Yoshikawa
Kazuaki
K
Nishikawa
Shin-Ichi
S
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D015870:Gene Expression; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012038:Regeneration / Q000235:genetics*
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C069766:necdin