Broad Center for Stem Cell Research and Jonsson Comprehensive Cancer Center
TheChuteLab
Research
Protein Tyrosine Phosphatase (PTP) Receptors in Regulating Stem Cell Fate
Recently, we discovered the function of protein tyrosine phosphatase – zeta (PTPζ), a member of the transmembrane PTP family, in regulating HSC self-renewal and regeneration (1-3). PTPζ is highly expressed by murine and human HSCs and is the receptor for pleiotrophin (PTN), a heparin binding growth factor which is secreted by bone marrow endothelial cells in the HSC vascular niche (1). PTN binding inhibits the phosphatase activity of PTPζ in HSCs, resulting in HSC self-renewal and expansion in vitro (1,2). Consistent with this observation, PTPζ-/- mice display significantly increased numbers of BM HSCs, progenitor cells and demonstrate increased HSC repopulating activity in competitive repopulation assays (2). We subsequently have discovered another PTP family member, PTPσ, which is highly expressed by murine and human HSCs at 100-fold higher levels than PTPζ. Interestingly, mice transplanted with PTPσ-/- BM cells display approximately 10-fold increased hematopoietic cell engraftment compared to mice transplanted with PTPσ+/+ BM cells. Similarly, human cord blood PTPσ-negative HSCs engraft NSG mice at 15-fold increased levels compared to PTPσ-expressing CB HSCs (4). We showed further that PTPσ inhibits the activation of the RhoGTPase, Rac1, in HSCs, and thereby serves as a negative regulator of HSC engraftment capacity (4). Pharmacologic inhibition of Rac1 abrogates the functional advantage otherwise observed in PTPσ-/- HSCs.
Taken together, these studies reveal a heretofore unknown function of PTP transmembrane receptors in regulating HSC fate and provide new mechanistic targets for the development of therapeutics capable of augmenting hematopoiesis in patients.
1. Himburg H, Muramoto G, Daher P, Meadows S, Russell J, Doan P, Chi J, Salter A, Lento W, Reya T, Chao N, Chute JP. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nature Medicine 16:475-482, 2010.
2. Himburg HA, Harris JR, Ito T, Daher P, Russell JL, Quarmyne M, Doan PL, Helms K, Nakamura M, Fixsen E, Herradon G, Reya T, Chao NJ, Harroch S, Chute JP. Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. Cell Reports 2:964-975, 2012.
3. Himburg HA, Yan X, Doan PL, Quarmyne M, Micewicz E, McBride W, Chao NJ, Slamon DJ, Chute JP. Pleiotrophin mediates hematopoietic regeneration via activation of Ras. J Clin Invest 124:4753-4758, 2014.
4. Quarmyne M, Doan PL, Himburg HA, Yan X, Nakamura M, Zhao L, Chao NJ, Chute JP. Protein tyrosine phosphatase-σ regulates hematopoietic stem cell repopulating capacity. J Clin Invest 2014 Epub ahead of print.
Recently, we discovered the function of protein tyrosine phosphatase – zeta (PTPζ), a member of the transmembrane PTP family, in regulating HSC self-renewal and regeneration (1-3). PTPζ is highly expressed by murine and human HSCs and is the receptor for pleiotrophin (PTN), a heparin binding growth factor which is secreted by bone marrow endothelial cells in the HSC vascular niche (1). PTN binding inhibits the phosphatase activity of PTPζ in HSCs, resulting in HSC self-renewal and expansion in vitro (1,2). Consistent with this observation, PTPζ-/- mice display significantly increased numbers of BM HSCs, progenitor cells and demonstrate increased HSC repopulating activity in competitive repopulation assays (2). We subsequently have discovered another PTP family member, PTPσ, which is highly expressed by murine and human HSCs at 100-fold higher levels than PTPζ. Interestingly, mice transplanted with PTPσ-/- BM cells display approximately 10-fold increased hematopoietic cell engraftment compared to mice transplanted with PTPσ+/+ BM cells. Similarly, human cord blood PTPσ-negative HSCs engraft NSG mice at 15-fold increased levels compared to PTPσ-expressing CB HSCs (4). We showed further that PTPσ inhibits the activation of the RhoGTPase, Rac1, in HSCs, and thereby serves as a negative regulator of HSC engraftment capacity (4). Pharmacologic inhibition of Rac1 abrogates the functional advantage otherwise observed in PTPσ-/- HSCs.
Taken together, these studies reveal a heretofore unknown function of PTP transmembrane receptors in regulating HSC fate and provide new mechanistic targets for the development of therapeutics capable of augmenting hematopoiesis in patients.
1. Himburg H, Muramoto G, Daher P, Meadows S, Russell J, Doan P, Chi J, Salter A, Lento W, Reya T, Chao N, Chute JP. Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nature Medicine 16:475-482, 2010.
2. Himburg HA, Harris JR, Ito T, Daher P, Russell JL, Quarmyne M, Doan PL, Helms K, Nakamura M, Fixsen E, Herradon G, Reya T, Chao NJ, Harroch S, Chute JP. Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. Cell Reports 2:964-975, 2012.
3. Himburg HA, Yan X, Doan PL, Quarmyne M, Micewicz E, McBride W, Chao NJ, Slamon DJ, Chute JP. Pleiotrophin mediates hematopoietic regeneration via activation of Ras. J Clin Invest 124:4753-4758, 2014.
4. Quarmyne M, Doan PL, Himburg HA, Yan X, Nakamura M, Zhao L, Chao NJ, Chute JP. Protein tyrosine phosphatase-σ regulates hematopoietic stem cell repopulating capacity. J Clin Invest 2014 Epub ahead of print.