TY - JOUR
T1 - In vivo Partial Reprogramming by Bacteria Promotes Adult Liver Organ Growth without Fibrosis and Tumorigenesis
AU - Hess, Samuel
AU - Kendall, Timothy
AU - Pena, Maria
AU - Yamane, Keitaro
AU - Soong, Daniel
AU - Adams, Linda
AU - Truman, Richard
AU - Rambukkana, Anura
N1 - Funding Information:
We acknowledge Roena Stevenson, Judith Wiles, Rachel Walley, and Gregory McCormick for animal studies, and Lyndsey Boswell, Melanie McMillan, and Michael Millar (SuRF@Little France) for histology and imaging. We thank Yanggu Shi and the bioinformatics team at Arraystar (Rockville, MD, USA), Jaminson McCorrison and John Glass (J Craig Venter Institute, CA, USA), and Rahul Sharma (National Hansen's Disease Program [NHDP]) for sequencing assistance, and David Hay and Luke Boulter (University of Edinburgh) for antibodies. We acknowledge Julia Martina-Rambukkana for generating illustrations from up-to-date literature. This work was supported by the Medical Research Council UK (MR/P011292/1 to A.R.) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases through Interagency Agreement AAI15006 with the Health Resources and Services Administration, Healthcare Systems Bureau, and National Hansen's Disease Program (R.T. and L.A.). T.J.K. was supported by a Wellcome Trust Intermediate Clinical Fellowship (095898/Z/11/Z). A.R. conceived the concept and designed the experimental strategy with S.H. T.J.K. D.S. and M.P. S.H. T.J.K. M.P. D.S. K.Y. and A.R. analyzed the data. M.P. selected and organized nine-banded armadillos for the study and collected and analyzed animal data under the supervision of R.T. L.A. and A.R. T.J.K. designed and performed the histopathological evaluation and quantification. D.S. performed machine-learning analysis and quantification of the data. S.H. and K.Y. performed the immunolabeling, imaging, and western blotting. A.R. S.H. and T.J.K. wrote the paper with contributions from M.P. and D.S. All authors read and approved the manuscript. T.J.K. undertakes consultancy work for Resolution Therapeutics.
Funding Information:
We acknowledge Roena Stevenson, Judith Wiles, Rachel Walley, and Gregory McCormick for animal studies, and Lyndsey Boswell, Melanie McMillan, and Michael Millar (SuRF@Little France) for histology and imaging. We thank Yanggu Shi and the bioinformatics team at Arraystar (Rockville, MD, USA), Jaminson McCorrison and John Glass (J Craig Venter Institute, CA, USA), and Rahul Sharma (National Hansen’s Disease Program [NHDP]) for sequencing assistance, and David Hay and Luke Boulter (University of Edinburgh) for antibodies. We acknowledge Julia Martina-Rambukkana for generating illustrations from up-to-date literature. This work was supported by the Medical Research Council UK ( MR/P011292/1 to A.R.) and the National Institutes of Health , National Institute of Allergy and Infectious Diseases through Interagency Agreement AAI15006 with the Health Resources and Services Administration , Healthcare Systems Bureau, and National Hansen’s Disease Program (R.T. and L.A.). T.J.K. was supported by a Wellcome Trust Intermediate Clinical Fellowship ( 095898/Z/11/Z ).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/11/15
Y1 - 2022/11/15
N2 - Ideal therapies for regenerative medicine or healthy aging require healthy organ growth and rejuvenation but no organ level approach is currently available. Using Mycobacterium leprae (ML) with natural partial cellular reprogramming capacity and its animal host nine-banded armadillos, we present an evolutionarily refined model of adult liver growth and regeneration. In infected-armadillos, ML reprogram the entire liver and significantly increase total liver: body weight by increasing healthy liver lobules including hepatocyte proliferation and proportionate expansion of vasculature, and biliary systems. ML infected livers are microarchitecturally and functionally normal without damage, fibrosis or tumorigenesis. Bacterial-induced reprogramming reactivates liver progenitor/developmental/fetal genes, and upregulates growth-, metabolism-, and anti-aging-associated markers with minimal change in senescence and tumorigenic genes, suggesting bacterial hijacking of homeostatic, regeneration pathways to promote de novo organogenesis. This may facilitate the unravelling endogenous pathways that effectively and safely re-engage liver organ growth, with broad therapeutic implications including organ regeneration and rejuvenation
AB - Ideal therapies for regenerative medicine or healthy aging require healthy organ growth and rejuvenation but no organ level approach is currently available. Using Mycobacterium leprae (ML) with natural partial cellular reprogramming capacity and its animal host nine-banded armadillos, we present an evolutionarily refined model of adult liver growth and regeneration. In infected-armadillos, ML reprogram the entire liver and significantly increase total liver: body weight by increasing healthy liver lobules including hepatocyte proliferation and proportionate expansion of vasculature, and biliary systems. ML infected livers are microarchitecturally and functionally normal without damage, fibrosis or tumorigenesis. Bacterial-induced reprogramming reactivates liver progenitor/developmental/fetal genes, and upregulates growth-, metabolism-, and anti-aging-associated markers with minimal change in senescence and tumorigenic genes, suggesting bacterial hijacking of homeostatic, regeneration pathways to promote de novo organogenesis. This may facilitate the unravelling endogenous pathways that effectively and safely re-engage liver organ growth, with broad therapeutic implications including organ regeneration and rejuvenation
U2 - 10.1016/j.xcrm.2022.100820
DO - 10.1016/j.xcrm.2022.100820
M3 - Article
SN - 2666-3791
VL - 3
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 11
M1 - 100820
ER -