Abstract
Degeneration of normal hematopoietic cells is a shared feature of malignant diseases in the hematopoietic system. Previous studies have shown the exhaustion of hematopoietic progenitor cells (HPCs) in leukemic marrow, whereas hematopoietic stem cells (HSCs) remain functional upon relocation to non-leukemic marrow. However, the underlying cellular mechanisms, especially the specific niche components that are responsible for the degeneration of HPCs, are unknown. In this study, we focused on murine bone mesenchymal stem cells (MSCs) and their supporting function for normal hematopoietic cells in Notch1-induced acute T-cell lymphocytic leukemia (T-ALL) mice. We demonstrate that the proliferative capability and differentiation potential of T-ALL MSCs were impaired due to accelerated cellular senescence. RNA-seq analysis revealed significant transcriptional alterations in leukemic MSCs. After co-cultured with the MSCs from T-ALL mice, a specific inhibitory effect on HPCs was defined, whereas in vivo repopulating potential of normal HSCs was not compromised. Furthermore, osteoprotegerin was identified as a cytokine to improve the function of T-ALL MSCs and to enhance normal HPC output via the p38/ERK pathway. Therefore, this study reveals a novel cellular mechanism underlying the inhibition of HPC generation in T-ALL. Leukemic MSCs may serve as a cellular target for improving normal hematopoietic regeneration therapeutically.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Williams DA, Cancelas JA . Leukaemia: niche retreats for stem cells. Nature 2006; 444: 827–828.
Morrison SJ, Scadden DT . The bone marrow niche for haematopoietic stem cells. Nature 2014; 505: 327–334.
Lymperi S, Ferraro F, Scadden DT . The HSC niche concept has turned 31. Has our knowledge matured? Ann NY Acad Sci 2010; 1192: 12–18.
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: 841–846.
Ding L, Saunders TL, Enikolopov G, Morrison SJ . Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 2012; 481: 457–462.
Mendelson A, Frenette PS . Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 2014; 20: 833–846.
Sorrentino A, Ferracin M, Castelli G, Biffoni M, Tomaselli G, Baiocchi M et al. Isolation and characterization of CD146+ multipotent mesenchymal stromal cells. Exp Hematol 2008; 36: 1035–1046.
Cheng T . Toward 'SMART' stem cells. Gene Ther 2008; 15: 67–73.
Dexter TM, Wright EG, Krizsa F, Lajtha LG . Regulation of haemopoietic stem cell proliferation in long term bone marrow cultures. Biomedicine 1977; 27: 344–349.
Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 2012; 10: 259–272.
Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466: 829–834.
Morikawa S, Mabuchi Y, Kubota Y, Nagai Y, Niibe K, Hiratsu E et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med 2009; 206: 2483–2496.
Hu X, Shen H, Tian C, Yu H, Zheng G, XuFeng R et al. Kinetics of normal hematopoietic stem and progenitor cells in a Notch1-induced leukemia model. Blood 2009; 114: 3783–3792.
Hu X, Shen H, Yu H, Xu F, Wang J, Cheng T Limited Regeneration but Functional Preservation of Hematopoietic Stem Cells in the Mice Developing Leukemia via Constitutive Expression of Notch1. ASH Annual Meeting Abstracts, 16 November 2007; 110: 204.
Miraki-Moud F, Anjos-Afonso F, Hodby KA, Griessinger E, Rosignoli G, Lillington D et al. Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proc Natl Acad Sci USA 2013; 110: 13576–13581.
Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D, Means TK et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 2005; 435: 969–973.
Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 2012; 21: 577–592.
Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA . Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 2008; 322: 1861–1865.
Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M, Garg T et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 2013; 13: 285–299.
Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisaki Y et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 2014; 15: 365–375.
Ma S, Shi Y, Pang Y, Dong F, Cheng H, Hao S et al. Notch1-induced T cell leukemia can be potentiated by microenvironmental cues in the spleen. J Hematol Oncol 2014; 7: 71.
Houlihan DD, Mabuchi Y, Morikawa S, Niibe K, Araki D, Suzuki S et al. Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-alpha. Nat Protoc 2012; 7: 2103–2111.
Lo Celso C, Klein RJ, Scadden DT . Analysis of the hematopoietic stem cell niche. Curr Protoc Stem Cell Biol 2007; Chapter 2: Unit 2A 5.
Ozenne P, Eymin B, Brambilla E, Gazzeri S . The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer 2010; 127: 2239–2247.
Charbord P, Pouget C, Binder H, Dumont F, Stik G, Levy P et al. A systems biology approach for defining the molecular framework of the hematopoietic stem cell niche. Cell Stem Cell 2014; 15: 376–391.
Purton LE, Scadden DT . Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 2007; 1: 263–270.
Song Y, Bahnson A, Hall N, Yu H, Shen H, Koebler D et al. Stem cell traits in long-term co-culture revealed by time-lapse imaging. Leukemia 2010; 24: 153–161.
Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T . Enrichment and characterization of murine hematopoietic stem cells that express c-kit molecule. Blood 1991; 78: 1706–1712.
Venezia TA, Merchant AA, Ramos CA, Whitehouse NL, Young AS, Shaw CA et al. Molecular signatures of proliferation and quiescence in hematopoietic stem cells. PLoS Biol 2004; 2: e301.
Wei Y, Ma D, Gao Y, Zhang C, Wang L, Liu F . Ncor2 is required for hematopoietic stem cell emergence by inhibiting Fos signaling in zebrafish. Blood 2014; 124: 1578–1585.
Simone MD, De Santis S, Vigneti E, Papa G, Amadori S, Aloe L . Nerve growth factor: a survey of activity on immune and hematopoietic cells. Hematol Oncol 1999; 17: 1–10.
Schweikle E, Baessler T, Yildirim S, Kanz L, Mohle R, Weisel KC . Osteoprotegerin positively regulates hematopoietic progenitor cells. Curr Stem Cell Res Ther 2012; 7: 72–77.
Durand C, Robin C, Bollerot K, Baron MH, Ottersbach K, Dzierzak E . Embryonic stromal clones reveal developmental regulators of definitive hematopoietic stem cells. Proc Natl Acad Sci USA 2007; 104: 20838–20843.
Conforti A, Biagini S, Del Bufalo F, Sirleto P, Angioni A, Starc N et al. Biological, functional and genetic characterization of bone marrow-derived mesenchymal stromal cells from pediatric patients affected by acute lymphoblastic leukemia. PLoS ONE 2013; 8: e76989.
Vicente Lopez A, Vazquez Garcia MN, Melen GJ, Entrena Martinez A, Cubillo Moreno I, Garcia-Castro J et al. Mesenchymal stromal cells derived from the bone marrow of acute lymphoblastic leukemia patients show altered BMP4 production: correlations with the course of disease. PLoS ONE 2014; 9: e84496.
Shibata KR, Aoyama T, Shima Y, Fukiage K, Otsuka S, Furu M et al. Expression of the p16INK4A gene is associated closely with senescence of human mesenchymal stem cells and is potentially silenced by DNA methylation during in vitro expansion. Stem Cells 2007; 25: 2371–2382.
Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 2006; 443: 421–426.
Beausejour CM, Campisi J . Ageing: balancing regeneration and cancer. Nature 2006; 443: 404–405.
Zhao H, Liu X, Zou H, Dai N, Yao L, Gao Q et al. Osteoprotegerin induces podosome disassembly in osteoclasts through calcium, ERK, and p38 MAPK signaling pathways. Cytokine 2015; 71: 199–206.
Huan J, Hornick NI, Goloviznina NA, Kamimae-Lanning AN, David LL, Wilmarth PA et al. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia 2015; e-pub ahead of print 25 June 2015; doi:10.1038/leu.2015.163.
Acknowledgements
We would like to thank Drs David T Scadden, Paul S Frenette and Tsvee Lapidot for their valuable input on this work. We are also grateful to our lab members and collaborators for assisting with the experiments and with the manuscript preparation. This study was supported by grants from the Ministry of Science and Technology of China (2011CB964801, 2012CB966601 and 2013CB966902) and from the National Natural Science Foundation of China (81090411, 81421002, 81330015, 81300374, 81300375, and 81430004).
Author contributions
ML and YP designed and performed the experiments, analyzed data and wrote the paper. SM and SH performed Fluidigm microfluidic chips for qRT-PCR. YZ, CH and XG helped isolate PαS MSCs and LSK cells. WY and FY helped analyze data and assisted with the manuscripts. TC conceived the study, designed the experiments, interpreted the results, wrote the paper and oversaw the research project.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Leukemia website
Rights and permissions
About this article
Cite this article
Lim, M., Pang, Y., Ma, S. et al. Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia 30, 154–162 (2016). https://doi.org/10.1038/leu.2015.210
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2015.210
This article is cited by
-
RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment
Leukemia (2024)
-
Mesenchymal PGD2 activates an ILC2-Treg axis to promote proliferation of normal and malignant HSPCs
Leukemia (2020)
-
Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment
Leukemia (2020)
-
Transmissible ER stress reconfigures the AML bone marrow compartment
Leukemia (2019)
-
Intravenous injection of allogeneic umbilical cord-derived multipotent mesenchymal stromal cells reduces the infarct area and ameliorates cardiac function in a porcine model of acute myocardial infarction
Stem Cell Research & Therapy (2018)