Details

Autor(en) / Beteiligte

• Quarmyne, Mamle
• Doan, Phuong L.
• Himburg, Heather A.
• Yan, Xiao
• Zhao, Liman
• Chao, Nelson J.
• Chute, John P.

Titel

Protein Tyrosine Phosphatase-Sigma (PTPσ) Regulates Hematopoietic Stem Cell Repopulating Capacity

Ist Teil von

• Blood, 2014-12, Vol.124 (21), p.4309-4309

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2014

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Hematopoietic stem cell (HSC) proliferation, differentiation and self-renewal are regulated by signaling through receptor tyrosine kinases (RTKs) such as c-kit, Flt-3 and Tie2. The functions of receptor protein tyrosine phosphatases (RPTPs) in counterbalancing RTK signaling in HSCs remain incompletely understood. Among 9 examined RPTPs, we found that PTP-sigma (PTPσ) was significantly overexpressed in mouse and human HSCs compared to more mature hematopoietic cells. PTPσ-/- mice displayed no difference in mature blood counts or phenotypic HSC frequency compared to PTPσ+/+ mice. However, competitive transplantation of BM cells from PTPσ-/- mice resulted in greater than 8-fold increased multilineage hematopoietic repopulation in primary and secondary recipient mice compared to mice transplanted with BM from PTPσ+/+ mice. While HSCs from PTPσ-/- mice displayed no differences in cell cycle status or homing capability compared to PTPσ+/+ mice, PTPσ-/- HSCs expressed significantly increased levels of activated Rac1, a RhoGTPase which regulates HSC engraftment capacity, compared to PTPσ+/+ BM cells. PTPσ-/- BM cells also displayed significantly increased transendothelial migration capacity and cobblestone area forming cells (CAFCs), consistent with increased Rac1 activation. Furthermore, Rac inhibition abrogated the increased migration capacity of PTPσ-/- BM cells, suggesting that the augmented engraftment capacity of PTPσ-/- BM cells was mediated via Rac activation. Translationally, we demonstrate that negative selection of human cord blood CD34+CD38-CD45RA-Lin- cells for PTPσ expression yielded a 15-fold enrichment for human long-term repopulating HSCs compared to CD34+CD38-CD45RA-Lin- cells or CD34+CD38-CD45RA-lin-PTPσ+ cells. These data suggest that PTPσ regulates HSC repopulating capacity via inhibition of Rac1 and that selection for human PTPσ - negative HSCs is a translatable strategy to significantly enrich human HSCs for transplantation. No relevant conflicts of interest to declare.