Article thumbnail

The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche

By Biquan Luo, Ben S. Lam, Sung Hyung Lee, Shiuan Wey, Hui Zhou, Miao Wang, Si-Yi Chen, Gregor B. Adams and Amy S. Lee


Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2008). B- and Tcell development both involve activity of the unfolded protein response pathway.
  2. (2005). Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche.
  3. (2003). Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
  4. (2009). Bone and blood vessels: the hard and the soft of hematopoietic stem cell niches.
  5. (2006). Cancer stem cells.
  6. (2002). Cell fate determination from stem cells.
  7. (2008). Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation.
  8. (2006). Differential role for very late antigen-5 in mobilization and homing of hematopoietic stem cells.
  9. (2007). Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches.
  10. (2001). Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability.
  11. (2008). Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes Bcell function via chaperoning integrin and TLR but not immunoglobulin.
  12. (2007). ER chaperones in mammalian development and human diseases.
  13. (2010). Essential role of the unfolded protein response regulator GRP78/BiP in protection from neuronal apoptosis.
  14. (2004). Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells.
  15. (2006). Glucose regulated proteins in cancer progression, drug resistance and immunotherapy.
  16. (2010). Gp93, the Drosophila GRP94 ortholog, is required for gut epithelial homeostasis and nutrient assimilation-coupled growth control.
  17. (2010). gp96, an endoplasmic reticulum master chaperone for integrins and Toll-like receptors, selectively regulates early T and B lymphopoiesis.
  18. (2010). GRP94 in ER quality control and stress responses.
  19. (2007). GRP94 is essential for mesoderm induction and muscle development because it regulates insulin-like growth factor secretion.
  20. Has our knowledge matured?
  21. (2007). Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages.
  22. (2002). Hematopoietic cytokines, transcription factors and lineage commitment.
  23. (1988). Hematopoietic microenvironment. Origin, lineage, and transplantability of the stromal cells in long-term bone marrow cultures from chimeric mice.
  24. (2008). Hematopoietic stem cell quiescence is maintained by compound contributions of the retinoblastoma gene family.
  25. (2000). Hematopoietic stem cell quiescence maintained by p21cip1/waf1.
  26. (2007). Hematopoietic stem cell trafficking: regulated adhesion and attraction to bone marrow microenvironment.
  27. (2007). Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum.
  28. (2003). Identification of the haematopoietic stem cell niche and control of the niche size.
  29. (2004). In vivo selfrenewing divisions of haematopoietic stem cells are increased in the absence of the early G1-phase inhibitor, p18INK4C.
  30. (1995). Inducible gene targeting in mice.
  31. (2008). Intrinsic and extrinsic control of haematopoietic stem-cell selfrenewal.
  32. (2003). ISO: a critical evaluation of the role of peptides in heat shock/chaperone protein-mediated tumor rejection.
  33. (2006). Lack of alpha4 integrin expression in stem cells restricts competitive function and selfrenewal activity.
  34. (2009). Liveanimal tracking of individual haematopoietic stem/progenitor cells in their niche.
  35. (2011). Loss of Cxcl12/ Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/ progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression.
  36. (2008). No place like home: anatomy and function of the stem cell niche.
  37. (2009). On the adaptation of endosteal stem cell niche function in response to stress.
  38. (2003). Osteoblastic cells regulate the haematopoietic stem cell niche.
  39. (2005). Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size.
  40. (2005). Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells.
  41. (2009). Parsing the niche code: the molecular mechanisms governing hematopoietic stem cell adhesion and differentiation.
  42. (2006). Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.
  43. (2006). PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention.
  44. (2008). Pten null prostate tumorigenesis and AKT activation are blocked by targeted knockout of ER chaperone GRP78/BiP in prostate epithelium.
  45. (2010). Re-examination of CD91 function in GRP94 (glycoprotein 96) surface binding, uptake, and peptide cross-presentation.
  46. (2009). Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator
  47. (2001). Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches.
  48. (2010). Targeted mutation of the mouse Grp94 gene disrupts development and perturbs endoplasmic reticulum stress signaling.
  49. (2006). The hematopoietic stem cell in its place.
  50. (2010). The HSC niche concept has turned
  51. (2006). The stem cell niches in bone.
  52. (2008). The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells.
  53. (2005). The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis.
  54. (2006). Therapeutic cancer vaccines.
  55. (2004). Tie2/ angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.
  56. (2008). Toward ‘SMART’ stem cells.
  57. (2004). Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells.
  58. (2006). Trumpp A
  59. (2008). Uncertainty in the niches that maintain haematopoietic stem cells.