OSTM1 Bone Defect Reveals an Intercellular Hematopoietic Crosstalk

The most severe form of bone autosomal recessive osteopetrosis both in humans and in the gray-lethal (gl/gl) mouse is caused by mutations in the Ostm1 gene. Although osteopetrosis is usually associated with a defect in the hematopoietic-derived osteoclast cells, this study determined that Ostm1 is expressed in many hematopoietic cells of the myeloid and lymphoid B- and T-lineages. Hematopoiesis in gl/gl mice is characterized by a marked expansion of the osteoclast lineage but also by deregulation of the lymphoid lineages with a decrease in B-lymphoid cell populations and altered distribution in T-lymphoid double and single CD4 CD8-positive cells. In committed gl/gl osteoclasts, specific Ostm1 transgene targeting showed a requirement of additional factors and/or cells for normal osteoclast function, and importantly, defined the gl osteopetrotic defect as non-cell autonomous. By contrast, gl/gl osteoclast, B- and T-lymphoid lineage phenotypes were rescued when Ostm1 is expressed under PU.1 regulation from a bacterial artificial chromosome transgene, which established an essential role for Ostm1 in hematopoietic cells in addition to osteoclasts. Together these experiments are the first to demonstrate the existence of hematopoietic crosstalk for the production of functional and active osteoclasts. The most severe form of bone autosomal recessive osteopetrosis both in humans and in the gray-lethal (gl/gl) mouse is caused by mutations in the Ostm1 gene. Although osteopetrosis is usually associated with a defect in the hematopoietic-derived osteoclast cells, this study determined that Ostm1 is expressed in many hematopoietic cells of the myeloid and lymphoid B- and T-lineages. Hematopoiesis in gl/gl mice is characterized by a marked expansion of the osteoclast lineage but also by deregulation of the lymphoid lineages with a decrease in B-lymphoid cell populations and altered distribution in T-lymphoid double and single CD4 CD8-positive cells. In committed gl/gl osteoclasts, specific Ostm1 transgene targeting showed a requirement of additional factors and/or cells for normal osteoclast function, and importantly, defined the gl osteopetrotic defect as non-cell autonomous. By contrast, gl/gl osteoclast, B- and T-lymphoid lineage phenotypes were rescued when Ostm1 is expressed under PU.1 regulation from a bacterial artificial chromosome transgene, which established an essential role for Ostm1 in hematopoietic cells in addition to osteoclasts. Together these experiments are the first to demonstrate the existence of hematopoietic crosstalk for the production of functional and active osteoclasts. A strict balance between bone formation and resorption in vertebrates is required throughout adult life to maintain a constant bone mass (1Teitelbaum S.L. Ross P. Nat. Rev. Genet. 2003; 4: 638-649Crossref PubMed Scopus (1321) Google Scholar, 2Boyle W.J. Simonet W.S. Lacey D.L. Nature. 2003; 423: 337-342Crossref PubMed Scopus (4981) Google Scholar, 3Zaidi M. Nat. Med. 2007; 13: 791-801Crossref PubMed Scopus (793) Google Scholar). The cells responsible for bone resorption are the osteoclasts that are formed through the fusion of hematopoietic myeloid cells. Failure of appropriate hematopoietic progenitors to differentiate or to mature into functional osteoclasts results in abnormal accumulation of mineralized osteoid and leads to osteopetrosis (4Janssens K. Van Hul W. Hum. Mol. Genet. 2002; 11: 2385-2393Crossref PubMed Scopus (55) Google Scholar). Severe human osteopetrosis is characterized by dense sclerotic bone, accumulation of mineralized osteoid and cartilage (5Lazner F. Gowen M. 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Fasth A. Friedrich W. Morgan G. Padmos A. Vellodi A. Porras O. O'Meara A. Porta F. Bordigoni P. Cant A. Hermans J. Griscelli C. Fisher A. J. Pediatr. 1994; 125: 896-902Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 11Eapen M. Davies S.M. Ramsay N.K.C. Orchard P.J. Bone Marrow Transplant. 1998; 22: 941-946Crossref PubMed Scopus (34) Google Scholar). Allogeneic bone marrow transplantation is possible for these patients, but this approach has major limitations. Alternatively, autologous hematopoietic stem cell transplantation upon gene therapy correction could circumvent these drawbacks. However, development of gene therapy protocols requires proper knowledge of hematopoiesis in osteopetrotic disorders. At present only mutation in OSTM1 and in three other genes, TCIRG1, ClCN7, and RANKL have been directly associated with severe autosomal recessive osteopetrosis in human (12Sobacchi C. Frattini A. Guerrini M.M. Abinun M. Pangrazio A. Susani L. Bredius R. Mancini G. Cant A. Bishop N. Grabowski P. Del Fattore A. Messina C. Errigo G. Coxon F.P. Scott D.I. Teti A. Rogers M.J. Vezzoni P. Villa A. Helfrich M.H. Nat. Genet. 2007; 39: 960-962Crossref PubMed Scopus (330) Google Scholar, 13Sobacchi C. Frattini A. Orchard P. Porras O. Tezcan I. Andolina M. Babul-Hirji R. Baric I. Canham N. Chitayat D. Dupuis-Girod S. Ellis I. Etzioni A. Fasth A. Fisher A. Gerristen B. Gulino V. Horwitz E. Klamroth V. Lanino E. Mirolo M. Musio A. Matthijs G. Nonomaya S. Notarangelo L.D. Ochs H.D. Furga A.S. Valiaho J. van Hove J.L.K. Vihinen M. Vujic D. Vezzoni P. Villa A. Hum. Mol. Genet. 2001; 10: 1767-1773Crossref PubMed Scopus (190) Google Scholar, 14Michigami T. Kageyama T. Satomura K. Yamaoka K. Nakayama M. Ozono K. Bone. 2002; 30: 436-439Crossref PubMed Scopus (43) Google Scholar, 15Scimeca J.-C. Quincey D. Parinello H. Romatet D. Grogeorges J. Gaudray P. Philip N. Fisher A. Carle G.F. Hum. Mut. 2003; 21: 151-157Crossref PubMed Scopus (51) Google Scholar, 16Kornak U. Kasper D. Bösl M.R. Kaiser E. Schweizer M. Schulz A. Friedrich W. Delling G. Jentsch T.J. Cell. 2001; 104: 205-215Abstract Full Text Full Text PDF PubMed Scopus (822) Google Scholar). The human OSTM1 gene has been characterized, and OSTM1 patients display the most severe recessive osteopetrotic phenotype and die at early ages (17Chalhoub N. Benachenhou N. Rajapurohitam V. Pata M. Ferron M. Frattini A. Villa A. Vacher J. Nat. Med. 2003; 9: 399-406Crossref PubMed Scopus (224) Google Scholar, 18Quarello P. Forni M. Barbereis L. Defilippi C. Campagnoli M.F. Frattini A. Chalhoub N. Vacher J. Ramenghi U. J. Bone Miner. Res. 2004; 19: 1194-1199Crossref PubMed Scopus (51) Google Scholar, 19Maranda B. Chabot G. Décarie J.-C. Pata M. Azeddine B. Moreau A. Vacher J. J. Bone Miner. Res. 2008; 23: 296-300Crossref PubMed Scopus (41) Google Scholar). Osteopetrotic mouse mutations have been characterized and associated with osteoclast differentiation or activation defects, including numerous transcription factors, such as PU.1, that play a crucial role in osteoclast lineage differentiation (20Tondravi M.M. McKercher S.R. Anderson K. Erdmann J.M. Quiroz M. Maki R. Teitelbaum S.L. Nature. 1997; 386: 81-84Crossref PubMed Scopus (454) Google Scholar), as well as proteins important in osteoclast activation, the murine Ostm1 (21Rajapurohitam V. Chalhoub N. Benachenhou N. Neff L. Baron R. Vacher J. Bone. 2001; 28: 513-523Crossref PubMed Scopus (49) Google Scholar). This murine Ostm1 gene was first identified in the gray-lethal (gl) 2The abbreviations used are: gl, gray-lethal mouse; BAC, bacterial artificial chromosome; TRAP, tartrate-resistant acid phosphatase; OCLs, osteoclast-like cells; FACS, fluorescence-activated cell sorting; hGH, human growth hormone; CFU-E, erythroid colony-forming units; CFU-GM, granulocyte-macrophage CFUs; CFU-M, macrophage CFUs; CFU-GEMM, granulocyte, erythroid, macrophage, and megakaryocyte CFUs. mouse mutant (17Chalhoub N. Benachenhou N. Rajapurohitam V. Pata M. Ferron M. Frattini A. Villa A. Vacher J. Nat. Med. 2003; 9: 399-406Crossref PubMed Scopus (224) Google Scholar) and encodes a unique transcript. Based on protein structural analysis, the Ostm1 protein likely corresponds to a type I transmembrane protein (17Chalhoub N. Benachenhou N. Rajapurohitam V. Pata M. Ferron M. Frattini A. Villa A. Vacher J. Nat. Med. 2003; 9: 399-406Crossref PubMed Scopus (224) Google Scholar). The gl mutation consists of a deletion that results in a null phenotype with absence of transcript and protein expression. gl mice produce osteoclasts, defined by multinucleated cells positive for the classic TRAP marker, but which are functionally inactive (21Rajapurohitam V. Chalhoub N. Benachenhou N. Neff L. Baron R. Vacher J. Bone. 2001; 28: 513-523Crossref PubMed Scopus (49) Google Scholar). Interestingly, gl mice demonstrated a significant increase in the mature bone-resident osteoclast population (21Rajapurohitam V. Chalhoub N. Benachenhou N. Neff L. Baron R. Vacher J. Bone. 2001; 28: 513-523Crossref PubMed Scopus (49) Google Scholar). Although the osteoclast defects in gl mice have been well analyzed histologically and ex vivo, it is important for the design of appropriate therapeutic approaches, for example autologous gene therapy, to understand the fundamental hematopoietic cellular defects and the role of Ostm1 in hematopoietic lineage differentiation and maturation. This study first characterized, in gl/gl hematopoietic phenotypes, an expansion of the osteoclast lineage as a compensatory mechanism and major lymphopoiesis anomalies with reduced B-lymphoid cell population and altered T-lymphoid cell differentiation pattern. Second, our results on Ostm1 hematopoietic-targeted transgenic mice support that Ostm1 is required not only in osteoclast lineage but also in other lineages to fully rescue gl/gl osteopetrosis and defective hematopoiesis. The mouse strain GL/Le dlJ +/+gl was obtained from The Jackson Laboratory (Bar Harbor, ME) and maintained by heterozygous brother × sister mating for ∼150 generations. Homozygous gl/gl mice used for analysis had a healthy appearance. Experiments with animals complied and were approved by the institutional animal care committee and Canadian Committee for Animal Protection. TRAP-Ostm1—The TRAP-Ostm1 construction was produced with the Ostm1 cDNA (1.055 kb) linked to the TRAP promoter (1.8 kb, XhoI/XbaI) upstream (22Reddy S.V. Scarcez T. Windle J.J. Leach R.J. Hundley J.E. Chirgwin J.M. Chou J.Y. Roodman G.D. J. Bone Min. Res. 1993; 8: 1263-1270Crossref PubMed Scopus (39) Google Scholar), and to the human hGH poly(A) signal (2.1 kb) downstream. Linearized transgene (XhoI/NotI) was injected into fertilized oocytes from F2 (C3H × C57BL/6) (23Ferron M. Vacher J. Genesis. 2005; 41: 138-145Crossref PubMed Scopus Google Scholar). mice were identified by with TRAP and Ostm1 were by of for for and for and were determined by transgenic was with heterozygous mice to gl/gl TRAP-Ostm1 transgenic PU.1 were first from a mouse on of upstream of PU.1 with at and the PU.1 with and analysis, of these kb) was for experiments and of PU.1 the PU.1 gene as well as the gene. targeting for were produced in to the PU.1 The first was to the gene from the on of the were from PU.1 and in S. C. N. Res. 2002; PubMed Scopus Google Scholar). The was to the PU.1 by the Ostm1 and an poly(A) PU.1 and were from the PU.1 and upstream and of the in the of the was used in a for S. C. N. Res. 2002; PubMed Scopus Google Scholar). The gene was from the PU.1 the The PU.1 were by of Ostm1 in the the At the were fully characterized by and and PU.1 were to proper gene and other The kb) was (17Chalhoub N. Benachenhou N. Rajapurohitam V. Pata M. Ferron M. Frattini A. Villa A. Vacher J. Nat. Med. 2003; 9: 399-406Crossref PubMed Scopus (224) Google Scholar), and transgenic were identified by PU.1 and Ostm1 were by of for for and for and transgene and were determined by was with heterozygous mice to gl/gl transgenic from gl/gl and mice was obtained by and into analysis was a cell with the mouse of The and were as of to were on and bone marrow single cell in with cells × were with or CD4 and with and were analyzed on a with of cells was from single cell in murine of and × F. J. Cell. 83: PubMed Scopus Google Scholar). was in and colony-forming were defined by and colony-forming were at granulocyte-macrophage colony-forming and macrophage colony-forming were at and granulocyte, erythroid, macrophage, and megakaryocyte colony-forming at macrophage cells were ex from bone marrow cells for in essential with and cells were from bone macrophage cell differentiation in for in essential with and of Alternatively, were ex by of with bone cells as (21Rajapurohitam V. Chalhoub N. Benachenhou N. Neff L. Baron R. Vacher J. Bone. 2001; 28: 513-523Crossref PubMed Scopus (49) Google Scholar). from OCLs, hematopoietic cells, and including bone and were with transgene was determined by on of The used Ostm1 and TRAP-Ostm1 transgene, gene and were for by of for for and for transgene was determined by on of The used were for Ostm1 and transgene, and PU.1 and and were in in a were by of for for and for in an Bone from mice were in in and in were with and and was are expressed as was used for analysis with Ostm1 was determined in mature hematopoietic cells from myeloid and lymphoid ex hematopoietic cell populations were obtained from bone and cells D. A. J. 2001; PubMed Scopus Google Scholar, D. J. S. A. J. Med. 1999; PubMed Scopus Google Scholar). analysis of Ostm1 showed high in and cells and in cells and to that Ostm1 could play a role in hematopoietic cell and in gl/gl the of the gl mutation on hematopoietic cell of gl/gl and The gl/gl mice showed a significant reduction in the of cells with as well as a significant reduction in and a In the of cells and was and in gl/gl mice Homozygous gl/gl mice a to to mice of the not of the or cell and not of (gl/gl) in a hematopoietic progenitors in of (gl/gl) in a of of gl gl/gl mice altered hematopoietic populations of gl/gl mice were is a of bone marrow cells in this severe osteopetrotic The of cell population in gl/gl and mice was not erythroid differentiation by early and cell populations in gl/gl mice the anemia, significant increase to In contrast, gl/gl mice showed a marked expansion of granulocyte-macrophage progenitors from which osteoclasts are to The of in gl/gl mice with mice but maintained In the of the cells, from which are were in gl/gl and that only the are and the osteoclast cell analysis on cell populations and in the analysis a significant increase of and cells that osteoclast, macrophage, and populations in gl/gl mice to In the cell was in gl/gl with progenitors By contrast, analysis of the population of cells was in gl/gl mice not myeloid and lymphoid cell populations of (gl/gl) in a gl gl/gl mice have reduced cell and human osteopetrotic patients have susceptibility to to altered the lymphoid lineages were in gl/gl and of the B-lymphoid cell population by a significant decrease of of the cell population in the gl/gl mice with the mature cell population was also reduced in gl/gl mice the B-lymphoid is of and cell populations Rev. 1993; 11: PubMed Scopus Google Scholar), have the cell population the specific to differentiation In gl/gl the cells that differentiate from bone marrow were reduced to mice The gl/gl was in to and the of to was reduced of the major populations in gl/gl and animals showed altered cellular Although the gl/gl double cell was an important in the double positive was determined to type the gl/gl mice a major to increase in single and CD8-positive cells cell analysis and altered distribution in cell populations of (gl/gl) in a In gl/gl the and mature osteoclast with inactive osteoclasts (21Rajapurohitam V. Chalhoub N. Benachenhou N. Neff L. Baron R. Vacher J. Bone. 2001; 28: 513-523Crossref PubMed Scopus (49) Google Scholar), that Ostm1 was required in committed of the osteoclast this transgenic mice Ostm1 under the of the committed osteoclasts TRAP gene promoter were TRAP-Ostm1 transgenic transgene were for and differentiation of the transgene was in and and in from showed and differentiation as not the TRAP-Ostm1 transgenic mice not bone The TRAP-Ostm1 transgenic mice from the three to for osteopetrosis by mating to heterozygous gl/gl TRAP-Ostm1 mice from these were for the Ostm1 mutation (17Chalhoub N. Benachenhou N. Rajapurohitam V. Pata M. Ferron M. Frattini A. Villa A. Vacher J. Nat. Med. 2003; 9: 399-406Crossref PubMed Scopus (224) Google Scholar) and the gl/gl TRAP-Ostm1 transgenic an osteopetrotic phenotype to gl/gl mice with reduced bone marrow and of This that Ostm1 in committed osteoclast to mature cells is not to rescue the gl/gl osteoclast of in gl/gl TRAP-Ostm1 transgenic mice and the lineage defects in gl/gl mice that Ostm1 is required in other hematopoietic cell or lineage at the PU.1 is essential in the early osteoclast lineage as well as in early hematopoietic including and lymphoid lineages (20Tondravi M.M. McKercher S.R. Anderson K. Erdmann J.M. Quiroz M. Maki R. Teitelbaum S.L. Nature. 1997; 386: 81-84Crossref PubMed Scopus (454) Google Scholar, G. 1999; Scholar), of the PU.1 gene were to Ostm1 in transgenic A PU.1 was that with the C. I. 2007; PubMed Scopus (91) Google Scholar), upstream of PU.1 essential for in transgenic mice P. H. K. M.J. McKercher S.R. Maki 2001; PubMed Scopus Google Scholar, G. F. H. K. F. P. B. Mol. 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This PU.1 was by The first the gene kb) to have PU.1 gene in the This was to a of to the PU.1 by that of Ostm1 The of PU.1 and of as determined by analysis and transgenic were between and of the in these and was by analysis of and with specific and not was in of transgenic but at a with Ostm1 in transgenic and in In the bone and and had A and In to Ostm1 and PU.1 transgene were but a as PU.1 A and in bone marrow also showed ex as for the PU.1, and TRAP from transgenic bone marrow and were produced at as not transgenic mice not functionally the transgene could rescue gl/gl three transgenic and were to heterozygous gl/gl mice from these were at the Ostm1 and for the Although gl/gl the gl osteopetrotic phenotypes, gl/gl transgenic from the three and appropriate bone marrow for functional rescue of the of gl/gl hematopoiesis defects was in gl/gl transgenic the myeloid and lymphoid cell populations of transgenic and gl/gl mice from transgenic and were by In transgenic gl/gl and cell populations showed to these populations were in gl/gl correction of the myeloid population was obtained with both transgenic of transgenic bone marrow cell populations also showed for the osteoclast In the mature cell populations in transgenic gl/gl in and bone marrow to in to gl/gl Interestingly, the and the cellular distribution of single and double lymphoid cell populations in gl/gl transgenic were from and that the had fully rescued gl/gl of B- and T-lymphoid cell populations in gl/gl transgenic cells × not not in a Ostm1 mutations to the most severe form of bone autosomal recessive osteopetrotic in both humans and gl/gl mice and are associated with a defect in the hematopoietic osteoclast Ostm1 analysis also in myeloid and lymphoid lineages and when in gl mice in altered hematopoietic differentiation and/or with anemia, and of Ostm1 in by targeting to the gl/gl committed osteoclasts the existence of additional factors or cells essential for osteoclast functional these established a non-cell mechanism for the gl by early hematopoietic Ostm1 in gl/gl mice determined that Ostm1 is required in other hematopoietic cells, including osteoclast for osteoclast demonstrated that Ostm1 a major role in and lymphopoiesis and of a crosstalk mechanism between hematopoietic cells for osteoclast of severe and in gl/gl mice to defective hematopoietic hematopoietic anomalies were likely of the early hematopoietic this population in gl/gl mice was The erythroid lineage differentiation of the early and progenitors that gl results from to the reduced By contrast, the gl/gl CFU-GM, from which the osteoclasts are were the committed that to but not to osteoclasts 1997; Google Scholar, C. N. Roodman G.D. Res. 2000; PubMed Scopus Google Scholar), were a marked expansion of early and osteoclast in gl/gl appropriate osteoclast lineage differentiation This increase in osteoclast progenitors and with the of mature gl/gl osteoclasts (21Rajapurohitam V. Chalhoub N. Benachenhou N. Neff L. Baron R. Vacher J. Bone. 2001; 28: 513-523Crossref PubMed Scopus (49) Google Scholar). of cell populations throughout the gl/gl osteoclast lineage to the mature cells the existence of a compensatory mechanism in to the inactive osteoclasts. In addition to the osteoclast lineage the gl/gl lymphoid cell differentiation is The reduced cell in were with decrease and mature B-lymphoid cell populations in gl/gl reduction in was in at at of in the other osteopetrotic mice including and H. T. H. O. T. T. L.D. 2000; PubMed Google Scholar, C. A. N. Carle G.F. 2004; PubMed Scopus Google Scholar, I. 1994; PubMed Scopus Google Scholar). Although these have and it that reduced population is a of osteopetrosis and to the absence of bone marrow as a for this However, the results of reduced cell population in gl/gl of the marrow and of the cell population support the that the differentiation the phenotype in gl/gl mice from and of Ostm1 in and on bone produce an of G. H. 2007; PubMed Scopus Google Scholar), such a decrease in population is likely to on and responsible for the osteoclast cell population of gl/gl to the the gl/gl cell population was reduced and also an altered distribution pattern. the of the gl/gl double cell population with the double positive population that Ostm1 is important these differentiation The significant increase in gl/gl mature CD4 and single positive cell populations with the decrease in double positive cells, as in osteopetrotic mice and H. T. H. O. T. T. L.D. 2000; PubMed Google Scholar, C. A. N. Carle G.F. 2004; PubMed Scopus Google Scholar). This cellular differentiation could an to maintain Alternatively, Ostm1 under normal could the positive mechanism of differentiation from the S. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). Together this hematopoietic of gl/gl mice Ostm1 in lineage differentiation at and/or mature cellular important from the study of transgenic Ostm1 in mice to gl/gl committed and mature inactive osteoclasts was the absence of osteoclast TRAP-Ostm1 transgene in gl/gl mature osteoclasts, gl/gl TRAP-Ostm1 transgenic severe osteopetrosis to the gl/gl This that the gl osteoclast defect is non-cell autonomous. with osteopetrotic phenotype caused by the of the a of Ostm1 in mature osteoclasts P. L. Jentsch T. J. Nature. PubMed Scopus Google Scholar). In of with the TRAP in transgenic as used for Ostm1 on a was to produce active osteoclasts and rescue osteopetrosis D. R. O. O. K. A. M. R. Schweizer M. U. Jentsch T.J. J. 2005; PubMed Scopus Google Scholar). analysis that the of Ostm1 is not only in but also in a hematopoietic cellular and a The hematopoietic rescue by the Ostm1 in PU.1 transgenic of the gl/gl mice is with a non-cell defect for the osteoclast and an essential role for Ostm1 in hematopoietic cell gl/gl transgenic mice demonstrated rescue of gl/gl osteopetrosis and hematopoietic defects with a of transgene expression. This correction additional and that Ostm1 is the gene responsible for the gl importantly, these results with of TRAP-Ostm1 showed that Ostm1 in a from the myeloid and/or lymphoid lineages to correction of the osteoclast activation In of hematopoietic cell type in gl osteopetrosis is with a rescue of gl phenotype by bone marrow transplantation PubMed Scopus Google Scholar). other osteoclasts, cellular essential for osteoclast activation, have been experiments the essential for osteoclast to and cells that are early and/or G. 1999; Scholar, S.L. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). Based on Ostm1 type I transmembrane the cellular likely or factors for osteoclast Although and from hematopoietic cells J. J. 2000; PubMed Scopus Google Scholar, R. Rev. 2005; PubMed Scopus Google Scholar) and are for have been or in cell to for osteoclast that Ostm1 in a cell with a of hematopoietic and factors that a crosstalk mechanism for osteoclast Based on this autologous gene therapy for osteopetrosis design to hematopoietic lineages for correction of the In of Ostm1 in deregulation of hematopoietic lineages in addition to osteoclast The osteopetrotic phenotype with Ostm1 to gl/gl osteoclasts gl defect non-cell autonomous. of gl/gl osteopetrosis by targeting Ostm1 to early hematopoietic lineages that Ostm1 is essential in early to produce functional mature osteoclasts. importantly, these have identified a hematopoietic crosstalk M. E. N. A. and D. Roodman for with

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