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Vascular and perivascular niches, but not the osteoblastic niche, are numerically restored following allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia

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Abstract

Bone marrow (BM) niches, including the osteoblastic, vascular, and perivascular niches, are numerically impaired in patients with aplastic anemia (AA). It remains unclear whether these niches are numerically restored in AA patients after allogenic hematopoietic stem cell transplantation (allo-HSCT). To investigate changes in BM niches, we monitored 52 patients with AA who had undergone allo-HSCT and performed immunohistochemical studies of BM niches using antibodies against CD34, CD146, and osteopontin. After allo-HSCT, patients with AA exhibited a remarkable increase in the number of cellular elements in the BM niches, including the vascular and perivascular cells. However, no significant differences in endosteal cells were detected. We explored the cause of this restoration by analyzing the origin of BM mesenchymal stem cells (BM-MSCs) and the expression of cytokines in BM plasma. STR-PCR revealed that the BM-MSCs were derived from the host, not the donor. In addition, significantly elevated levels of vascular endothelial growth factor (VEGF) were found after allo-HSCT. Our data indicates that vascular and perivascular niches are numerically restored, but the endosteal niche remains numerically impaired in patients with AA after allo-HSCT, and that levels of VEGF, but not donor-derived BM-MSCs, may correlate with the restoration of BM niches.

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Fig. 1

The Fig. 1 (b1) was derived from our previous paper [1]

Fig. 2

The control data of this figure, including Fig. 2a, b and c, was derived from our previous paper [1]

Fig. 3
Fig. 4

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References

  1. Wu L, Mo W, Zhang Y, Deng H, Li Y, Zhou R, et al. Impairment of hematopoietic stem cell niches in patients with aplastic anemia. Int J Hematol. 2015;102:645–53.

    Article  CAS  PubMed  Google Scholar 

  2. Fureder W, Krauth MT, Sperr WR, Sonneck K, Simonitsch-Klupp I, Mullauer L, et al. Evaluation of angiogenesis and vascular endothelial growth factor expression in the bone marrow of patients with aplastic anemia. Am J Pathol. 2006;168:123–30.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Holmberg LA, Seidel K, Leisenring W, Torok-Storb B. Aplastic anemia: analysis of stromal cell function in long-term marrow cultures. Blood. 1994;84:3685–90.

    CAS  PubMed  Google Scholar 

  4. Shipounova IN, Petrova TV, Svinareva DA, Momotuk KS, Mikhailova EA, Drize NI. Alterations in hematopoietic microenvironment in patients with aplastic anemia. Clin Transl Sci. 2009;2:67–74.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wu L, Mo W, Zhang Y, Wang S. Vascular and perivascular niches but not osteoblastic niche restoration in patients with aplastic anemia after allogeneic hematopoietic stem cell transplantation by dynamic observation. Bone Marrow Transpl. 2016;51(Suppl 1):S473 (poster 672).

    Google Scholar 

  6. Park M, Park CJ, Jang S, Kim DY, Lee JH, Lee JH, et al. Reduced expression of osteonectin and increased natural killer cells may contribute to the pathophysiology of aplastic anemia. Appl Immunohistochem Mol Morphol. 2015;23:139–45.

    Article  CAS  PubMed  Google Scholar 

  7. Michelozzi IM, Pievani A, Pagni F, Antolini L, Verna M, Corti P, et al. Human aplastic anaemia-derived mesenchymal stromal cells form functional haematopoietic stem cell niche in vivo. Br J Haematol. 2016. doi:10.1111/bjh.14234.

  8. Kopp HG, Avecilla ST, Hooper AT, Rafii S. The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiol (Bethesda). 2005;20:349–56.

    Article  CAS  Google Scholar 

  9. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481:457–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.

    Article  CAS  PubMed  Google Scholar 

  11. Boulais PE, Frenette PS. Making sense of hematopoietic stem cell niches. Blood. 2015;125:2621–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131:324–36.

    Article  CAS  PubMed  Google Scholar 

  13. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chuncharunee S, Wong R, Rojnuckarin P, Chang CS, Chang KM, Lu MY, et al. Efficacy of rabbit antithymocyte globulin as first-line treatment of severe aplastic anemia: an Asian multicenter retrospective study. Int J Hematol. 2016;104:454–61.

    Article  CAS  PubMed  Google Scholar 

  15. Miano M, Dufour C. The diagnosis and treatment of aplastic anemia: a review. Int J Hematol. 2015;101:527–35.

    Article  CAS  PubMed  Google Scholar 

  16. Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147:43–70.

    Article  CAS  PubMed  Google Scholar 

  17. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. Consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15:825–8.

    CAS  Google Scholar 

  18. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transpl. 2005;11:945–56.

    Article  Google Scholar 

  19. Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol. 1997;150:815–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bartsch K, Al-Ali H, Reinhardt A, Franke C, Hudecek M, Kamprad M, et al. Mesenchymal stem cells remain host-derived independent of the source of the stem-cell graft and conditioning regimen used. Transplantation. 2009;87:217–21.

    Article  PubMed  Google Scholar 

  21. Villaron EM, Almeida J, Lopez-Holgado N, Alcoceba M, Sanchez-Abarca LI, Sanchez-Guijo FM, et al. Mesenchymal stem cells are present in peripheral blood and can engraft after allogeneic hematopoietic stem cell transplantation. Haematologica. 2004;89:1421–7.

    PubMed  Google Scholar 

  22. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  CAS  PubMed  Google Scholar 

  23. Bueno C, Roldan M, Anguita E, Romero-Moya D, Martin-Antonio B, Rosu-Myles M, et al. Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease. Haematologica. 2014;99:1168–75.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Zaim M, Karaman S, Cetin G, Isik S. Donor age and long-term culture affect differentiation and proliferation of human bone marrow mesenchymal stem cells. Ann Hematol. 2012;91:1175–86.

    Article  PubMed  Google Scholar 

  25. Purton LE, Mielcarek M, Torok-Storb B. Monocytes are the likely candidate ‘stromal’ cell in G-CSF-mobilized peripheral blood. Bone Marrow Transpl. 1998;21:1075–6.

    Article  CAS  Google Scholar 

  26. Odriozola A, Riancho JA, Colorado M, Zarrabeitia MT. Evaluation of the sensitivity of two recently developed STR multiplexes for the analysis of chimerism after haematopoietic stem cell transplantation. Int J Immunogenet. 2013;40:88–92.

    Article  CAS  PubMed  Google Scholar 

  27. Schraml E, Daxberger H, Watzinger F, Lion T. Quantitative analysis of chimerism after allogeneic stem cell transplantation by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection: the Vienna experience. Leukemia. 2003;17:224–7.

    Article  CAS  PubMed  Google Scholar 

  28. Bacigalupo A, Socie G, Hamladji RM, Aljurf M, Maschan A, Kyrcz-Krzemien S, et al. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis. Haematologica. 2015;100:696–702.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Maury S, Balere-Appert ML, Chir Z, Boiron JM, Galambrun C, Yakouben K, et al. Unrelated stem cell transplantation for severe acquired aplastic anemia: improved outcome in the era of high-resolution HLA matching between donor and recipient. Haematologica. 2007;92:589–96.

    Article  PubMed  Google Scholar 

  30. Xu LP, Wang SQ, Wu DP, Wang JM, Gao SJ, Jiang M, et al. Haplo-identical transplantation for acquired severe aplastic anaemia in a multicentre prospective study. Br J Haematol. 2016;175:265–74.

    Article  PubMed  Google Scholar 

  31. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85:221–8.

    Article  CAS  PubMed  Google Scholar 

  32. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.

    Article  CAS  PubMed  Google Scholar 

  33. Wei X, Liu C, Wang H, Wang L, **ao F, Guo Z, et al. Surface phosphatidylserine is responsible for the internalization on microvesicles derived from hypoxia-induced human bone marrow mesenchymal stem cells into human endothelial cells. PLoS One. 2016;11:e0147360.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5:434–8.

    Article  CAS  PubMed  Google Scholar 

  35. Kfoury Y, Scadden DT. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell. 2015;16:239–53.

    Article  CAS  PubMed  Google Scholar 

  36. Stute N, Fehse B, Schroder J, Arps S, Adamietz P, Held KR, et al. Human mesenchymal stem cells are not of donor origin in patients with severe aplastic anemia who underwent sex-mismatched allogeneic bone marrow transplant. J Hematother Stem Cell Res. 2002;11:977–84.

    Article  PubMed  Google Scholar 

  37. Wang J, Liu K, Lu DP. Mesenchymal stem cells in stem cell transplant recipients are damaged and remain of host origin. Int J Hematol. 2005;82:152–8.

    Article  PubMed  Google Scholar 

  38. Chen JL, Hunt P, McElvain M, Black T, Kaufman S, Choi ES. Osteoblast precursor cells are found in CD34 + cells from human bone marrow. Stem Cells. 1997;15:368–77.

    Article  CAS  PubMed  Google Scholar 

  39. Matsumoto T, Kawamoto A, Kuroda R, Ishikawa M, Mifune Y, Iwasaki H, et al. Therapeutic potential of vasculogenesis and osteogenesis promoted by peripheral blood CD34-positive cells for functional bone healing. Am J Pathol. 2006;169:1440–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457:92–6.

    Article  CAS  PubMed  Google Scholar 

  41. Gerber HP, Ferrara N. The role of VEGF in normal and neoplastic hematopoiesis. J Mol Med (Berl). 2003;81:20–31.

    Article  CAS  Google Scholar 

  42. Gianelli U, Vener C, Raviele PR, Savi F, Somalvico F, Calori R, et al. VEGF expression correlates with microvessel density in Philadelphia chromosome-negative chronic myeloproliferative disorders. Am J Clin Pathol. 2007;128:966–73.

    Article  PubMed  Google Scholar 

  43. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–8.

    Article  CAS  PubMed  Google Scholar 

  44. Salvucci O, Yao L, Villalba S, Sajewicz A, Pittaluga S, Tosato G. Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. Blood. 2002;99:2703–11.

    Article  CAS  PubMed  Google Scholar 

  45. Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ, Denhardt DT, et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood. 2005;106:1232–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to express gratitude for the excellent laboratory assistance of the pathologist Wei Xu. This work was supported by the Natural Science Foundation of Guangdong Province (2014A030313676), Guangzhou Municipal Science and Technology project (201508020254), Guangdong science and technology project (2014A020212521), the General guidance project of Guangzhou Health and Family Planning Commission (20161A011003) and the National Natural Science Foundation of China (81600147).

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    1. Department of Hematology, Guangzhou First People’s Hospital, Guangzhou Medical University, No.1 Panfu Road, Guangzhou, 510180, China

      Liangliang Wu, Wenjian Mo, Yu** Zhang, Ming Zhou, Yumiao Li, Ruiqing Zhou, Shiling Xu, Shiyi Pan, ** Mao & Shunqing Wang

    2. Department of Blood Transfusion, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China

      Hui Deng

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    L. Wu and W. Mo contributed equally to this work.

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    Wu, L., Mo, W., Zhang, Y. et al. Vascular and perivascular niches, but not the osteoblastic niche, are numerically restored following allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia. Int J Hematol 106, 71–81 (2017). https://doi.org/10.1007/s12185-017-2217-1

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