BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Impact of mesenchymal stem cell senescence on inflammaging

  • Lee, Byung-Chul (Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health) ;
  • Yu, Kyung-Rok (Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea)
  • Received : 2019.11.14
  • Published : 2020.02.29
Download PDF
⟨ Previous Next ⟩

Abstract

Life expectancy has dramatically increased around the world over the last few decades, and staying healthier longer, without chronic disease, has become an important issue. Although understanding aging is a grand challenge, our understanding of the mechanisms underlying the degeneration of cell and tissue functions with age and its contribution to chronic disease has greatly advanced during the past decade. As our immune system alters with aging, abnormal activation of immune cells leads to imbalance of innate and adaptive immunity and develops a persistent and mild systemic inflammation, inflammaging. With their unique therapeutic properties, such as immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have been considered to be a promising source for treating autoimmune disease or as anti-aging therapy. Although direct evidence of the role of MSCs in inflammaging has not been thoroughly studied, features reported in senescent MSCs or the aging process of MSCs are associated with inflammaging; MSC niche-driven skewing of hematopoiesis toward the myeloid lineage or oncogenesis, production of pro-inflammatory cytokines, and weakening their modulative property on macrophage polarization, which plays a central role on inflammaging development. This review explores the role of senescent MSCs as an important regulator for onset and progression of inflammaging and as an effective target for anti-aging strategies.

Keywords

References

  1. Kontis V, Bennett JE, Mathers CD, Li G, Foreman K and Ezzati M (2017) Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet 389, 1323-1335 https://doi.org/10.1016/S0140-6736(16)32381-9
  2. Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D and Capri M (2017) Immunobiography and the Heterogeneity of Immune Responses in the Elderly: A Focus on Inflammaging and Trained Immunity. Front Immunol 8, 982 https://doi.org/10.3389/fimmu.2017.00982
  3. Fulop T, Larbi A, Dupuis G et al (2017) Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol 8, 1960 https://doi.org/10.3389/fimmu.2017.01960
  4. Yu KR, Espinoza DA, Wu C et al (2018) The impact of aging on primate hematopoiesis as interrogated by clonal tracking. Blood 131, 1195-1205 https://doi.org/10.1182/blood-2017-08-802033
  5. Pang WW, Price EA, Sahoo D et al (2011) Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci U S A 108, 20012-20017 https://doi.org/10.1073/pnas.1116110108
  6. Derhovanessian E, Maier AB, Beck R et al (2010) Hallmark features of immunosenescence are absent in familial longevity. J Immunol 185, 4618-4624 https://doi.org/10.4049/jimmunol.1001629
  7. Smolen JS, Aletaha D and McInnes IB (2016) Rheumatoid arthritis. Lancet 388, 2023-2038 https://doi.org/10.1016/S0140-6736(16)30173-8
  8. Libby P, Ridker PM and Maseri A (2002) Inflammation and atherosclerosis. Circulation 105, 1135-1143 https://doi.org/10.1161/hc0902.104353
  9. Heppner FL, Ransohoff RM and Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16, 358-372 https://doi.org/10.1038/nrn3880
  10. Franceschi C, Bonafe M, Valensin S et al (2000) Inflammaging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908, 244-254 https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
  11. Fransen F, van Beek AA, Borghuis T et al (2017) Aged Gut Microbiota Contributes to Systemical Inflammaging after Transfer to Germ-Free Mice. Front Immunol 8, 1385 https://doi.org/10.3389/fimmu.2017.01385
  12. Calcada D, Vianello D, Giampieri E et al (2014) The role of low-grade inflammation and metabolic flexibility in aging and nutritional modulation thereof: a systems biology approach. Mech Ageing Dev 136-137, 138-147 https://doi.org/10.1016/j.mad.2014.01.004
  13. Yu KR and Kang KS (2013) Aging-related genes in mesenchymal stem cells: a mini-review. Gerontology 59, 557-563 https://doi.org/10.1159/000353857
  14. Yu KR, Lee JY, Kim HS et al (2014) A p38 MAPK-mediated alteration of COX-2/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell aging. PLoS One 9, e102426 https://doi.org/10.1371/journal.pone.0102426
  15. Badiavas AR and Badiavas EV (2011) Potential benefits of allogeneic bone marrow mesenchymal stem cells for wound healing. Expert Opin Biol Ther 11, 1447-1454 https://doi.org/10.1517/14712598.2011.606212
  16. Wagner W, Horn P, Castoldi M et al (2008) Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS One 3, e2213 https://doi.org/10.1371/journal.pone.0002213
  17. Yang YM, Li P, Cui DC et al (2015) Effect of aged bone marrow microenvironment on mesenchymal stem cell migration. Age (Dordr) 37, 16 https://doi.org/10.1007/s11357-014-9743-z
  18. Franceschi C, Garagnani P, Vitale G, Capri M and Salvioli S (2017) Inflammaging and 'Garb-aging'. Trends Endocrinol Metab 28, 199-212 https://doi.org/10.1016/j.tem.2016.09.005
  19. Franceschi C and Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to ageassociated diseases. J Gerontol A Biol Sci Med Sci 69 Suppl 1, S4-9 https://doi.org/10.1093/gerona/glu057
  20. Robbins PD (2017) Extracellular vesicles and aging. Stem Cell Investig 4, 98 https://doi.org/10.21037/sci.2017.12.03
  21. Agarwal S and Busse PJ (2010) Innate and adaptive immunosenescence. Ann Allergy Asthma Immunol 104, 183-190; quiz 190-182, 210 https://doi.org/10.1016/j.anai.2009.11.009
  22. Franceschi C, Garagnani P, Parini P, Giuliani C and Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14, 576 https://doi.org/10.1038/s41574-018-0059-4
  23. Frasca D and Blomberg BB (2016) Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology 17, 7-19 https://doi.org/10.1007/s10522-015-9578-8
  24. Martucci M, Ostan R, Biondi F et al (2017) Mediterranean diet and inflammaging within the hormesis paradigm. Nutr Rev 75, 442-455 https://doi.org/10.1093/nutrit/nux013
  25. Szarc vel Szic K, Declerck K, Vidakovic M and Vanden Berghe W (2015) From inflammaging to healthy aging by dietary lifestyle choices: is epigenetics the key to personalized nutrition? Clin Epigenetics 7, 33 https://doi.org/10.1186/s13148-015-0068-2
  26. Kang J, Park D, Shah M et al (2019) Lipopolysaccharide induces neuroglia activation and $NF-{\kappa}B$ activation in cerebral cortex of adult mice. Lab Anim Res 35, 19 doi:10.1186/s42826-019-0018-9
  27. Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K and Suuronen T (2008) Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res Rev 7, 83-105 https://doi.org/10.1016/j.arr.2007.09.002
  28. Chazaud B and Mouchiroud G (2014) Inflamm-aging: STAT3 signaling pushes muscle stem cells off balance. Cell Stem Cell 15, 401-402 https://doi.org/10.1016/j.stem.2014.09.010
  29. Latz E and Duewell P (2018) NLRP3 inflammasome activation in inflammaging. Semin Immunol 40, 61-73 https://doi.org/10.1016/j.smim.2018.09.001
  30. Salminen A, Kaarniranta K and Kauppinen A (2012) Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY) 4, 166-175 https://doi.org/10.18632/aging.100444
  31. Steele AK, Lee EJ, Vestal B et al (2014) Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature. PLoS One 9, e97171 https://doi.org/10.1371/journal.pone.0097171
  32. Kang I, Lee BC, Choi SW et al (2018) Donor-dependent variation of human umbilical cord blood mesenchymal stem cells in response to hypoxic preconditioning and amelioration of limb ischemia. Exp Mol Med 50, 35 https://doi.org/10.1038/s12276-017-0014-9
  33. Lee BC, Kim JJ, Lee JY et al (2019) Disease-specific primed human adult stem cells effectively ameliorate experimental atopic dermatitis in mice. Theranostics 9, 3608-3621 https://doi.org/10.7150/thno.32945
  34. Katakowski M, Buller B, Zheng X et al (2013) Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 335, 201-204 https://doi.org/10.1016/j.canlet.2013.02.019
  35. Lai RC, Arslan F, Lee MM et al (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4, 214-222 https://doi.org/10.1016/j.scr.2009.12.003
  36. de Witte SFH, Luk F, Sierra Parraga JM et al (2018) Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells. Stem Cells 36, 602-615 https://doi.org/10.1002/stem.2779
  37. Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A and Nikbin B (2006) Aging of mesenchymal stem cell in vitro. BMC Cell Biol 7, 14 https://doi.org/10.1186/1471-2121-7-14
  38. Li Y, Wu Q, Wang Y, Li L, Bu H and Bao J (2017) Senescence of mesenchymal stem cells (Review). Int J Mol Med 39, 775-782 https://doi.org/10.3892/ijmm.2017.2912
  39. Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF and Schmidt AM (2005) Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15, 16R-28R https://doi.org/10.1093/glycob/cwi053
  40. Pisetsky DS, Erlandsson-Harris H and Andersson U (2008) High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease. Arthritis Res Ther 10, 209 https://doi.org/10.1186/ar2440
  41. Salminen A, Ojala J, Kaarniranta K and Kauppinen A (2012) Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases. Cell Mol Life Sci 69, 2999-3013 https://doi.org/10.1007/s00018-012-0962-0
  42. Yeo RW, Lai RC, Zhang B et al (2013) Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev 65, 336-341 https://doi.org/10.1016/j.addr.2012.07.001
  43. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA and Mardani K (2012) Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett 147, 47-54 https://doi.org/10.1016/j.imlet.2012.06.001
  44. Lei Q, Liu T, Gao F et al (2017) Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells. Theranostics 7, 2673-2689 https://doi.org/10.7150/thno.18915
  45. Lehmann BD, Paine MS, Brooks AM et al (2008) Senescence-associated exosome release from human prostate cancer cells. Cancer Res 68, 7864-7871 https://doi.org/10.1158/0008-5472.CAN-07-6538
  46. Burger D, Kwart DG, Montezano AC et al (2012) Microparticles induce cell cycle arrest through redoxsensitive processes in endothelial cells: implications in vascular senescence. J Am Heart Assoc 1, e001842
  47. Peffers MJ, Collins J, Fang Y et al (2016) Age-related changes in mesenchymal stem cells identified using a multi-omics approach. Eur Cell Mater 31, 136-159 https://doi.org/10.22203/eCM.v031a10
  48. Fleshner M and Crane CR (2017) Exosomes, DAMPs and miRNA: Features of Stress Physiology and Immune Homeostasis. Trends Immunol 38, 768-776 https://doi.org/10.1016/j.it.2017.08.002
  49. Balasubramanyam M, Aravind S, Gokulakrishnan K et al (2011) Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes. Mol Cell Biochem 351, 197-205 https://doi.org/10.1007/s11010-011-0727-3
  50. de Haan G and Lazare SS (2018) Aging of hematopoietic stem cells. Blood 131, 479-487 https://doi.org/10.1182/blood-2017-06-746412
  51. Pang WW, Schrier SL and Weissman IL (2017) Age-associated changes in human hematopoietic stem cells. Semin Hematol 54, 39-42 https://doi.org/10.1053/j.seminhematol.2016.10.004
  52. Minciullo PL, Catalano A, Mandraffino G et al (2016) Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity. Arch Immunol Ther Exp (Warsz) 64, 111-126 https://doi.org/10.1007/s00005-015-0377-3
  53. Coppe JP, Desprez PY, Krtolica A and Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5, 99-118 https://doi.org/10.1146/annurev-pathol-121808-102144
  54. Mattiucci D, Maurizi G, Leoni P and Poloni A (2018) Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes. Cell Transplant 27, 754-764 https://doi.org/10.1177/0963689717745890
  55. Bonafe M, Storci G and Franceschi C (2012) Inflamm-aging of the stem cell niche: breast cancer as a paradigmatic example: breakdown of the multi-shell cytokine network fuels cancer in aged people. Bioessays 34, 40-49 https://doi.org/10.1002/bies.201100104
  56. Lepperdinger G (2011) Inflammation and mesenchymal stem cell aging. Curr Opin Immunol 23, 518-524 https://doi.org/10.1016/j.coi.2011.05.007
  57. Cartwright MJ, Tchkonia T and Kirkland JL (2007) Aging in adipocytes: potential impact of inherent, depot-specific mechanisms. Exp Gerontol 42, 463-471 https://doi.org/10.1016/j.exger.2007.03.003
  58. Starr ME, Evers BM and Saito H (2009) Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. J Gerontol A Biol Sci Med Sci 64, 723-730 https://doi.org/10.1093/gerona/glp046
  59. Romieu-Mourez R, Francois M, Boivin MN, Bouchentouf M, Spaner DE and Galipeau J (2009) Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol 182, 7963-7973 https://doi.org/10.4049/jimmunol.0803864
  60. Di GH, Liu Y, Lu Y, Liu J, Wu C and Duan HF (2014) IL-6 secreted from senescent mesenchymal stem cells promotes proliferation and migration of breast cancer cells. PLoS One 9, e113572 https://doi.org/10.1371/journal.pone.0113572
  61. O'Hagan-Wong K, Nadeau S, Carrier-Leclerc A et al (2016) Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells' homeostasis. Oncotarget 7, 13285-13296 https://doi.org/10.18632/oncotarget.7690
  62. Carvalho JL, Braga VB, Melo MB et al (2013) Priming mesenchymal stem cells boosts stem cell therapy to treat myocardial infarction. J Cell Mol Med 17, 617-625 https://doi.org/10.1111/jcmm.12036
  63. Balandran JC, Purizaca J, Enciso J et al (2016) Proinflammatory-Related Loss of CXCL12 Niche Promotes Acute Lymphoblastic Leukemic Progression at the Expense of Normal Lymphopoiesis. Front Immunol 7, 666
  64. Oishi Y and Manabe I (2016) Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech Dis 2, 16018 https://doi.org/10.1038/npjamd.2016.18
  65. Shin TH, Kim HS, Kang TW et al (2016) Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis. Cell Death Dis 7, e2524 https://doi.org/10.1038/cddis.2016.442
  66. Pajarinen J, Lin T, Gibon E et al (2019) Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials 196, 80-89 https://doi.org/10.1016/j.biomaterials.2017.12.025
  67. Yin Y, Wu RX, He XT, Xu XY, Wang J and Chen FM (2017) Influences of age-related changes in mesenchymal stem cells on macrophages during in-vitro culture. Stem Cell Res Ther 8, 153 https://doi.org/10.1186/s13287-017-0608-0
  68. Kovtonyuk LV, Fritsch K, Feng X, Manz MG and Takizawa H (2016) Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment. Front Immunol 7, 502
  69. Shepherd MS and Kent DG (2019) Emerging single-cell tools are primed to reveal functional and molecular heterogeneity in malignant hematopoietic stem cells. Curr Opin Hematol 26, 214-221 https://doi.org/10.1097/MOH.0000000000000512
  70. Wilson NK, Kent DG, Buettner F et al (2015) Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem Cell Populations. Cell Stem Cell 16, 712-724 https://doi.org/10.1016/j.stem.2015.04.004
  71. Chen Z, Amro EM, Becker F et al (2019) Cohesin-mediated NF-kappaB signaling limits hematopoietic stem cell self-renewal in aging and inflammation. J Exp Med 216, 152-175 https://doi.org/10.1084/jem.20181505
  72. Geiger H, Denkinger M and Schirmbeck R (2014) Hematopoietic stem cell aging. Curr Opin Immunol 29, 86-92 https://doi.org/10.1016/j.coi.2014.05.002
  73. Linehan E, Dombrowski Y, Snoddy R, Fallon PG, Kissenpfennig A and Fitzgerald DC (2014) Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. Aging Cell 13, 699-708 https://doi.org/10.1111/acel.12223
  74. Lloberas J and Celada A (2002) Effect of aging on macrophage function. Exp Gerontol 37, 1325-1331 https://doi.org/10.1016/S0531-5565(02)00125-0
  75. Lim Z, Brand R, Martino R et al (2010) Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol 28, 405-411 https://doi.org/10.1200/JCO.2009.21.8073
  76. Gibson KL, Wu YC, Barnett Y et al (2009) B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 8, 18-25 https://doi.org/10.1111/j.1474-9726.2008.00443.x
  77. Castilho JL, Shepherd BE, Koethe J et al (2016) CD4+/CD8+ ratio, age, and risk of serious noncommunicable diseases in HIV-infected adults on antiretroviral therapy. AIDS 30, 899-908 https://doi.org/10.1097/QAD.0000000000001005
  78. Ghajar CM, Peinado H, Mori H et al (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 15, 807-817 https://doi.org/10.1038/ncb2767
  79. Zambetti NA, Ping Z, Chen S et al (2016) Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. Cell Stem Cell 19, 613-627 https://doi.org/10.1016/j.stem.2016.08.021
  80. Kim M, Kim C, Choi YS, Kim M, Park C and Suh Y (2012) Age-related alterations in mesenchymal stem cells related to shift in differentiation from osteogenic to adipogenic potential: implication to age-associated bone diseases and defects. Mech Ageing Dev 133, 215-225 https://doi.org/10.1016/j.mad.2012.03.014
  81. Justesen J, Stenderup K, Ebbesen EN, Mosekilde L, Steiniche T and Kassem M (2001) Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis. Biogerontology 2, 165-171 https://doi.org/10.1023/A:1011513223894
  82. Ambrosi TH, Scialdone A, Graja A et al (2017) Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. Cell Stem Cell 20, 771-784 e776 https://doi.org/10.1016/j.stem.2017.02.009
  83. Baker N, Boyette LB and Tuan RS (2015) Characterization of bone marrow-derived mesenchymal stem cells in aging. Bone 70, 37-47 https://doi.org/10.1016/j.bone.2014.10.014
  84. Bilwani FA and Knight KL (2012) Adipocyte-derived soluble factor(s) inhibits early stages of B lymphopoiesis. J Immunol 189, 4379-4386 https://doi.org/10.4049/jimmunol.1201176
  85. Ergen AV, Boles NC and Goodell MA (2012) Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 119, 2500-2509 https://doi.org/10.1182/blood-2011-11-391730
  86. Busque L, Patel JP, Figueroa ME et al (2012) Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44, 1179-1181 https://doi.org/10.1038/ng.2413
  87. Inoue S, Lemonnier F and Mak TW (2016) Roles of IDH1/2 and TET2 mutations in myeloid disorders. Int J Hematol 103, 627-633 https://doi.org/10.1007/s12185-016-1973-7
  88. Suijker J, Baelde HJ, Roelofs H, Cleton-Jansen AM and Bovee JV (2015) The oncometabolite D-2-hydroxyglutarate induced by mutant IDH1 or -2 blocks osteoblast differentiation in vitro and in vivo. Oncotarget 6, 14832-14842 https://doi.org/10.18632/oncotarget.4024
  89. Valli A, Harris AL and Kessler BM (2015) Hypoxia metabolism in ageing. Aging (Albany NY) 7, 465-466 https://doi.org/10.18632/aging.100782
  90. Intlekofer AM, Dematteo RG, Venneti S et al (2015) Hypoxia Induces Production of L-2-Hydroxyglutarate. Cell Metab 22, 304-311 https://doi.org/10.1016/j.cmet.2015.06.023
  91. Cicione C, Muinos-Lopez E, Hermida-Gomez T, Fuentes-Boquete I, Diaz-Prado S and Blanco FJ (2013) Effects of severe hypoxia on bone marrow mesenchymal stem cells differentiation potential. Stem Cells Int 2013, 232896 https://doi.org/10.1155/2013/232896
  92. Xing J, Ying Y, Mao C et al (2018) Hypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota. Nat Commun 9, 2020 https://doi.org/10.1038/s41467-018-04453-9
  93. Abdel-Wahab O, Adli M, LaFave LM et al (2012) ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 22, 180-193 https://doi.org/10.1016/j.ccr.2012.06.032
  94. Rohatgi N, Zou W, Collins PL et al (2018) ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1. Blood Adv 2, 2467-2477 https://doi.org/10.1182/bloodadvances.2018018309
  95. Uni M, Masamoto Y, Sato T et al (2019) Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. Leukemia 33, 191-204 https://doi.org/10.1038/s41375-018-0198-6
  96. Zhang P, Chen Z, Li R et al (2018) Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. Cell Discov 4, 4 https://doi.org/10.1038/s41421-017-0004-z
  97. Sun X, Hao H, Han Q et al (2017) Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance by suppressing NLRP3 inflammasome-mediated inflammation in type 2 diabetes rats. Stem Cell Res Ther 8, 241 https://doi.org/10.1186/s13287-017-0668-1
  98. Turinetto V, Vitale E and Giachino C (2016) Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy. Int J Mol Sci 17, 1164 https://doi.org/10.3390/ijms17071164