scholarly journals Erythropoietin signaling promotes transplanted progenitor cell survival

2009 ◽  
Vol 23 (9) ◽  
pp. 3089-3099 ◽  
Author(s):  
Yi Jia ◽  
Renaud Warin ◽  
Xiaobing Yu ◽  
Reed Epstein ◽  
Constance Tom Noguchi
2020 ◽  
Vol 14 ◽  
Author(s):  
Jixian Wang ◽  
Brian Wang ◽  
Lei Jiang ◽  
Kaijing Zhou ◽  
Guo-Yuan Yang ◽  
...  

2009 ◽  
pp. NA-NA ◽  
Author(s):  
Julia C. Knight ◽  
Eugene L. Scharf ◽  
Yang Mao-Draayer

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3859-3859
Author(s):  
Li ang Li ◽  
Tinisha McDonald ◽  
Hardik Modi ◽  
Arjun Sehgal ◽  
Ravi Bhatia

Abstract SHP-2 (ptpn11), a Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase, is expressed at high levels in hematopoietic cells and regulates downstream signaling from growth factor (GF) receptors. SHP-2 has been shown to play an important role in murine hematopoiesis. Moreover, several SHP-2 activating mutations have been identified in myeloid malignancies and there is interest in the development of SHP-2 inhibitors for cancer treatment. On the other hand previous report suggested that SHP-2 inhibition was associated with enhanced GF responsiveness in human hematopoietic cell lines. However the role of SHP-2 signaling in normal human hematopoietic stem and progenitor cell growth has not been studied. Here we investigated the function of SHP-2 in normal human hematopoiesis by inhibiting SHP-2 expression in cord blood (CB) CD34+ cells with stable SHP-2 shRNA expression. We transduced CB CD34+ cells with lentivirus vectors coexpressing SHP-2 specific shRNAs (Si-1 or Si-2) or a control shRNA (Ctrl) and RFP and selected RFP expressing CD34+ cells by flow cytometry sorting. We observed >80% inhibition of SHP-2 expression by Western blotting in Si-1 or Si-2 shRNA transduced cells compared with Ctrl shRNA transduced cells. We observed that culture with increasing concentrations of GF was associated with markedly reduced GF-induced stimulation of proliferation of SHP-2-knockdown CD34+ cells compared to controls. In addition we observed significantly increased apoptosis of SHP-2-knockdown CD34+ cells cultured under low and high GF conditions compared to controls, but little increase in apoptosis in GF-deprived cells, indicating markedly reduced response of SHP-2-knockdown cells to GF-mediated promotion of cell survival. SHP-2-knockdown CD34+ cells also demonstrated significantly reduced expansion in cell numbers following culture in high GF conditions compared with controls (115.3, 25.5 and 10.4 fold expansion for Ctrl, Si-1 and Si-2 at day 7). Analysis of the nature of cells generated in GF culture showed significantly reduced generation of both myeloid (CD33+, CD11b+ and CD14+) and erythroid cells from SHP-2-knockdown CD34+ cells compared with controls, with relatively greater inhibition of myeloid compared with erythroid differentiation. On the other hand CD34+ cell numbers were retained at levels similar to controls after culture. We also observed significantly reduced cell expansion and differentiation and higher apoptotic rates of SHP-2-knockdown cells cultured under either myeloid promoting (IL-3+SCF+G-CSF+GM-CSF) or erythroid promoting (SCF+EPO) GF conditions. SHP-2-knockdown cells demonstrated reduced activation of MAPK and STAT5 but not Akt on Western blotting that was associated with reduced MCL-1 expression, consistent with their reduced GF mediated proliferation and survival. Expression of the transcription factors SCL1, GATA-1, NF-E2 and FOG-1 was increased in SHP-2 knockdown CD34+ cells compared to controls, consistent with the relatively higher retention of CD34+ and erythroid cells compared with myeloid cells after culture. In conclusion, we show that SHP-2 knockdown in human CD34+ cells results in markedly decreased responsiveness to GF stimulation with significantly increased apoptosis, markedly diminished proliferation and reduced generation of differentiated cells during GF culture. A relative retention of the CD34+ cell population was seen despite increased apoptosis, which may be the result of reduced cell turnover and altered transcription factor expression in SHP-2-knockdown cells, and is in contrast to reduced stem cell self-renewal observed following SHP-2 knockdown in murine models. These results indicate a critical role for SHP-2 in GF mediated signaling responses in human hematopoietic stem/progenitor cells. These studies also caution that therapeutic SHP-2 inhibition could be associated with significant hematopoietic toxicity.


2009 ◽  
Vol 106 (42) ◽  
pp. 17763-17768 ◽  
Author(s):  
R. XuFeng ◽  
M. J. Boyer ◽  
H. Shen ◽  
Y. Li ◽  
H. Yu ◽  
...  

Haematologica ◽  
2015 ◽  
Vol 100 (11) ◽  
pp. 1396-1406 ◽  
Author(s):  
E. Heideveld ◽  
F. Masiello ◽  
M. Marra ◽  
F. Esteghamat ◽  
N. Ya c  ◽  
...  

Biomaterials ◽  
2013 ◽  
Vol 34 (16) ◽  
pp. 3992-4001 ◽  
Author(s):  
Kiryu K. Yap ◽  
Aaron M. Dingle ◽  
Jason A. Palmer ◽  
Raminder S. Dhillon ◽  
Zerina Lokmic ◽  
...  

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