{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:47:39Z","timestamp":1790189259989,"version":"4.1.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T00:00:00Z","timestamp":1723420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and aim<\/jats:title><jats:p>Bone marrow stem cells (BM-SCs) and their progeny play a central role in tissue repair and regeneration. In patients with chronic liver failure, bone marrow (BM) reserve is severally compromised and they showed marked defects in the resolution of injury and infection, leading to liver failure and the onset of decompensation. Whether BM failure is the cause or consequence of liver failure during cirrhosis is not known. In this study, we aimed to determine the underlying relationship between BM failure and regeneration failure in cirrhosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methodology<\/jats:title><jats:p>C57Bl\/6(J) mice were used to develop chronic liver injury through intra-peritoneal administration of carbon tetrachloride (CCl4) for 15 weeks (0.1-0.5 ml\/kg). Animals were sacrificed to study the transition of cirrhosis and BM defects. To restore the BM-SC reserve; healthy BM cells were infused via intra-BM infusion and assessed for changes in liver injury, regeneration, and BM-SC reserve.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using a CCl4-induced animal - model of cirrhosis, we showed the loss of BM-SCs reserve occurred before regeneration failure and the onset of non-acute decompensation. Intra-BM infusion of healthy BM cells induced the repopulation of native hematopoietic stem cells (HSCs) in cirrhotic BM. Restoring BM-HSCs reserve augments liver macrophage-mediated clearance of infection and inflammation dampens neutrophil-mediated inflammation, accelerates fibrosis regression, enhances hepatocyte proliferation, and delays the onset of non-acute decompensation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that loss of BM-HSCs reserve underlies the compromised innate immune function of the liver, drives regeneration failure, and the onset of non-acute decompensation. We further provide the proof-of-concept that rejuvenating BM-HSC reserve can serve as a potential therapeutic approach for preventing regeneration failure and transition to decompensated cirrhosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1439510","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T09:17:16Z","timestamp":1723454236000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Rejuvenating bone marrow hematopoietic reserve prevents regeneration failure and hepatic decompensation in animal model of cirrhosis"],"prefix":"10.3389","volume":"15","author":[{"given":"Nidhi","family":"Nautiyal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepanshu","family":"Maheshwari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhananjay","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Pranshu","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh Mani","family":"Tripathi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunidhi","family":"Diwakar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manisha","family":"Bhardwaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujata","family":"Mohanty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Baligar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupama","family":"Kumari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chhagan","family":"Bihari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhrajit","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. K.","family":"Sarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupam","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2005.10.013","article-title":"Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies","volume":"44","author":"D\u2019Amico","year":"2006","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2006.08.007","article-title":"Natural history of patients hospitalized for management of cirrhotic ascites","volume":"4","author":"Planas","year":"2006","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.jhep.2021.12.023","article-title":"Corrigendum to \u2018Towards a new definition of decompensated cirrhosis\u2019 [J Hepatol 76 (2022) 202-207]","volume":"76","author":"D\u2019Amico","year":"2022","journal-title":"J Hepatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/(ISSN)1527-3350","article-title":"Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis","volume":"8","author":"Schrier","year":"1988","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/hep.v27:5","article-title":"Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality","volume":"27","author":"Navasa","year":"1998","journal-title":"Hepatology"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.07.004","article-title":"Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis","volume":"63","author":"Bernardi","year":"2015","journal-title":"J Hepatol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.jhep.2013.07.044","article-title":"Pathological bacterial translocation in liver cirrhosis","volume":"60","author":"Wiest","year":"2014","journal-title":"J Hepatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2002.05791.x","article-title":"Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia","volume":"97","author":"Bauer","year":"2002","journal-title":"Am J Gastroenterol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"237ra66","DOI":"10.1126\/scitranslmed.3008618","article-title":"The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota","volume":"6","author":"Balmer","year":"2014","journal-title":"Sci Transl Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.33715","article-title":"Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites","volume":"36","author":"Such","year":"2002","journal-title":"Hepatology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2001.04668.x","article-title":"Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis","volume":"96","author":"Bauer","year":"2001","journal-title":"Am J Gastroenterol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.11.013","article-title":"Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice","volume":"72","author":"Xiang","year":"2020","journal-title":"J Hepatol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-021-10244-0","article-title":"Establishment of a murine model of acute-on-chronic liver failure with multi-organ dysfunction","volume":"15","author":"Nautiyal","year":"2021","journal-title":"Hepatol Int"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s12072-019-09983-y","article-title":"Cellular and functional loss of liver endothelial cells correlates with poor hepatocyte regeneration in acute-on-chronic liver failure","volume":"13","author":"Shubham","year":"2019","journal-title":"Hepatol Int"},{"key":"B15","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1053\/j.gastro.2017.03.022","article-title":"Sphingosine-1-phosphate prevents egress of hematopoietic stem cells from liver to reduce fibrosis","volume":"153","author":"King","year":"2017","journal-title":"Gastroenterology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.02.031","article-title":"Alternatively activated macrophages promote resolution of necrosis following acute liver injury","volume":"73","author":"Starkey Lewis","year":"2020","journal-title":"J Hepatol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2991","DOI":"10.1182\/blood-2011-12-380113","article-title":"Demand-adapted regulation of early hematopoiesis in infection and inflammation","volume":"119","author":"Takizawa","year":"2012","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1089\/wound.2021.0065","article-title":"Hematopoietic stem cells in wound healing response","volume":"11","author":"Urao","year":"2022","journal-title":"Adv Wound Care (New Rochelle)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2004.09.005","article-title":"G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs","volume":"33","author":"Yannaki","year":"2005","journal-title":"Exp Hematol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.cell.2017.11.034","article-title":"Modulation of myelopoiesis progenitors is an integral component of trained immunity","volume":"172","author":"Mitroulis","year":"2018","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.cell.2017.12.013","article-title":"Western diet triggers NLRP3-dependent innate immune reprogramming","volume":"172","author":"Christ","year":"2018","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.03.043","article-title":"Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities","volume":"185","author":"Li","year":"2022","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.05.003","article-title":"Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss","author":"Wang","year":"2024","journal-title":"Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00167","article-title":"Regulation of monocyte-macrophage responses in cirrhosis-role of innate immune programming and checkpoint receptors","volume":"10","author":"Riva","year":"2019","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3928323","DOI":"10.1155\/2021\/3928323","article-title":"Hyperlipidemia may synergize with hypomethylation in establishing trained immunity and promoting inflammation in NASH and NAFLD","volume":"2021","author":"Drummer","year":"2021","journal-title":"J Immunol Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.856587","article-title":"Bioenergetic failure drives functional exhaustion of monocytes in acute-on-chronic liver failure","volume":"13","author":"Maheshwari","year":"2022","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2013.12.010","article-title":"A novel mechanism of abnormal hematological indices in liver cirrhosis: bone marrow endothelial cell dysfunction caused by humoral inhibitor affects the hematopoietic function of bone marrow","volume":"82","author":"Gao","year":"2014","journal-title":"Med Hypotheses"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28754","article-title":"Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver","volume":"64","author":"Bihari","year":"2016","journal-title":"Hepatology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1234","article-title":"Suboptimal level of bone-forming cells in advanced cirrhosis are associated with hepatic osteodystrophy","volume":"2","author":"Bihari","year":"2018","journal-title":"Hepatol Commun"},{"key":"B30","first-page":"12","article-title":"Defects in energy metabolism are associated with functional exhaustion of bone marrow mesenchymal stem cells in cirrhosis","volume":"11","author":"Kumar","year":"2022","journal-title":"Am J Stem Cells"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.08.010","article-title":"Cirrhosis-associated immune dysfunction: Distinctive features and clinical relevance","volume":"61","author":"Albillos","year":"2014","journal-title":"J Hepatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/liv.13923","article-title":"Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis","volume":"39","author":"Anand","year":"2019","journal-title":"Liver Int"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.08.020","article-title":"Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche","volume":"22","author":"Luo","year":"2015","journal-title":"Cell Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.08.025","article-title":"Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment","volume":"131","author":"Sacchetti","year":"2007","journal-title":"Cell"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nature09262","article-title":"Mesenchymal and haematopoietic stem cells form a unique bone marrow niche","volume":"466","author":"M\u00e9ndez-","year":"2010","journal-title":"Nature"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.4993.626","article-title":"Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication","volume":"2","author":"Barnes","year":"1956","journal-title":"Br Med J"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01246","article-title":"Bone marrow transplantation 1957-2019","volume":"10","author":"Simpson","year":"2019","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/cmi.2011.53","article-title":"Liver fibrosis: mechanisms of immune-mediated liver injury","volume":"9","author":"Xu","year":"2012","journal-title":"Cell Mol Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1002\/hep.31759","article-title":"Gene deconvolution reveals aberrant liver regeneration and immune cell infiltration in alcohol-associated hepatitis","volume":"74","author":"Kim","year":"2021","journal-title":"Hepatology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.11.048","article-title":"The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis","volume":"74","author":"Arroyo","year":"2021","journal-title":"J Hepatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24315","article-title":"Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function","volume":"53","author":"Thomas","year":"2011","journal-title":"Hepatology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1186\/s13287-023-03569-0","article-title":"Repopulating Kupffer cells originate directly from hematopoietic stem cells","volume":"14","author":"Fan","year":"2023","journal-title":"Stem Cell Res Ther"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.02.014","article-title":"A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease","volume":"60","author":"Nishikawa","year":"2014","journal-title":"J Hepatol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13026","article-title":"Long-term repopulation of aged bone marrow stem cells using young Sca-1 cells promotes aged heart rejuvenation","volume":"18","author":"Li","year":"2019","journal-title":"Aging Cell"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1253\/circj.CJ-13-0267","article-title":"Bone marrow rejuvenation accelerates re-endothelialization and attenuates intimal hyperplasia after vascular injury in aging mice","volume":"77","author":"Wang","year":"2013","journal-title":"Circ J"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1038\/s41467-023-37783-4","article-title":"Restoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response","volume":"14","author":"Ramalingam","year":"2023","journal-title":"Nat Commun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022017514","article-title":"Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation","volume":"141","author":"Zeng","year":"2023","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1439510\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T09:17:21Z","timestamp":1723454241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1439510\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,12]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2024.1439510"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1439510","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,12]]},"article-number":"1439510"}}