Anura Rambukkana Research Group
Adult tissue cell plasticity, reprogramming and regeneration
Our laboratory uses a pioneering and disruptive approach to exploit the thematic intersection of the biology of bacterial-induced partial host cell reprogramming with regeneration and aging.
By harnessing naturally-occurring and evolutionarily refined bacterial strategies and using machine-learning/artificial intelligence tools our ultimate future goals are to develop new therapeutics for treating chronic human diseases affecting those tissues/organs with high regenerative capacity – the peripheral nerves, liver, skin and intestine. Our bacterial agents naturally target these tissues in their animal and human hosts promoting tissue growth and regeneration either by reprogramming cells or propagating existing tissue stem cells rendering them to a more “rejuvenated” or ‘youthful’ state.
Learning from this, our research focuses to translate bacterial mechanisms that engage these regenerative pathways into strategies to develop therapeutics that promote tissue repair in diseased or aging tissues/organs.
These bacterial strategies could inform the development of new therapeutic approaches to reprogram cancers into a less aggressive phenotype to promote patient survival.
Our discovery that strictly host-dependent bacterial pathogens like Mycobacterium leprae hijacks the notable plasticity of adult regenerative host tissues also holds promise for developing strategies for targeting key host-encoded functions of cell reprogramming as an alternative approach for combating bacterial infections, particularly the emerging global threat by drug/antibiotic-resistant bacteria.
“Look deep into Nature and you will understand everything Better” – Albert Einstein
"In every walk with Nature one receives far more than he seeks." - John Muir (Scottish-American naturalist)
Aims and areas of interest
Our laboratory studies a pioneering approach from a natural bacterial infection process with partial host cell reprogramming capacity to address the basic biology of adult tissue stem cells and their properties in regulating homeostasis, regeneration and rejuvenation of tissues. We seek to translate our discoveries to develop interventions for tissue repair and reversing the cellular aging process. Many years of our studies on the cell biology of Mycobacterium leprae infection of peripheral glial cells Schwann cells (highlighted in: Cell, 1997; 2000; Science, 1998; 2002; PNAS, 1999, 2005; Nature Medicine, 2006), led to the discovery that this bacterium has a striking capacity to naturally partially reprogram adult Schwann cells to stem cell-like cells (Cell, 2013). Building on this concept our current studies are focused on how this bacterial ingenuity of partially reprogram adult tissue cells to progenitor state can be exploited to regenerate diseased tissues and rejuvenate aging tissues.
We are also studying how these reprogrammed progenitor/stem cells can be combined with endogenous innate immune cells with natural regenerative and tissue protective properties to promote repair processes without adverse effects in tissues with high regenerative capacities, peripheral nerves, liver, skin and intestine in varying model systems, in vitro, ex vivo and in vivo models. These concepts have now translated to in vivo studies using larger mammals, nine-banded armadillo and pigs. Studies in nine-banded armadillos showed that bacteria employ their ingenuities of partial host cell reprogramming to promote the growth of adult liver at an organ level in living animals (Cell Rep Medicine, 2022). If we could detail the mechanism of how bacteria grow the adult liver as a functional organ without causing adverse effects in living animals, we may be able to translate that knowledge to develop safer therapeutic interventions to rejuvenate aging livers and to regenerate damaged tissues in humans in future. Learning from evolutionary refined bacterial strategies of tissue growth and regeneration our long-term goals are to develop common and safer interventions for therapeutic regeneration and rejuvenation for tissues/organs with high regenerative capacities, namely the peripheral nerves, liver, skin and intestine, where our bacterial models naturally target in their animal and human host.
Hess S, Kendall TJ, Pena M, Yamane K, Soong D, Adams L, Truman R, Rambukkana A. In vivo partial reprogramming by bacteria promotes adult liver organ growth without fibrosis and tumorigenesis. Cell Rep Medicine. 2022 Nov 15;3(11):100820. doi: 10.1016/j.xcrm.2022.100820.
Hess S, Rambukkana A. 2019. Cell biology of intracellular adaptation of Mycobacterium leprae in the peripheral nervous system. Microbiol Spectrum 7(4): BAI-0020-2019. doi:10.1128/microbiolspec.BAI-0020-2019.
Hess S, Rambukkana A. 2015. Bacterial-induced cell reprogramming to stem cell-like cells: new premise in host-pathogen interaction. Curr. Opin. Microbiol. Feb 23: 179-188.
Masaki T, McGlinchey A, Cholewa-Waclaw J, Qu J, Tomlinson SR, Rambukkana A. 2014. Innate Immune Response Precedes Mycobacterium leprae-Induced Reprogramming of Adult Schwann Cells. Cell Reprogram. 16(1):9-17. doi:10.1089/cell.2013.0064. Epub 2013 Nov 26.
Masaki T, Qu J, Cholewa-Waclaw J, Burr K, Raaum R, Rambukkana A. 2013. Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection. Cell 152(1):51-67.
Masaki T, Qu J, Cholewa-Waclaw J, Burr K, Raaum R, Rambukkana A. 2013. Reprogramming Adult Schwann Cells to Stem Cell-like Cells by Leprosy Bacilli Promotes Dissemination of Infection. Best of Cell 2013, online issue, 2014.
Tapinos N, Ohnishi M, Rambukkana A. 2006. ErbB2 receptor tyrosine kinase mediates early demyelination induced by leprosy bacilli. Nature Medicine 12:961-966.
Tapinos N, Rambukkana A. 2005. Insights into regulation of human Schwann cell proliferation by ERK-1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Proc. Natl. Acad. Sci. USA 102:9188-9193. See perspective in Science STKE. Nov 8:309, pe52.
Rambukkana A *, Kuntz, S, Min, J, Kampbell, KP. Oldstone, MB. 2003. Targeting Schwann cells by nonlytic arenaviral infection selectively inhibits myelination. Proc Natl Acad Sci USA.100: 16071-10676 (*corresponding author)
Rambukkana A*, Zanazzi G, Tapinos N, Salzer JL. 2002. Contact-dependent demyelination by Mycobacterium leprae in the absence of immune responses. Science 296:927-931. *corresponding author
Ng V, Zanazzi G, Salzer JL, Timpl R, Talts JF, Brennan P, Rambukkana A. 2000. Role of the cell wall Phenolic Glycolipid-1 in the peripheral nerve predilection of Mycobacterium leprae. Cell 103:511-524.
Shimoji Y, Ng V, Matsumura K, Fischetti VA, Rambukkana A: A novel surface protein of M. leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. Proc Natl Acd Sci.USA 96: 9857-9862, 1999.
Rambukkana A*, Yamada, H, Sanazzi, G, Salzer JL, Yurchenco PD, Campbell, KP 1998. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science 282: 2076-2079. (*corresponding author; Highlights in Perspectives and Mini review: “Wellcome Mat for Leprosy and Lassa Fever Virus; Science, 282, 1999, 1998; Dystroglycan versatility, Cell 97, 543-546, 1999).
Rambukkana A*, Salzer JL, Yurchenco PD, Tuomanen EI. 1997. Neural targeting Mycobacterium leprae Mediated by the G domain of the laminin alpha2 chain. Cell 88: 811-821 (*corresponding author).
Biography Prof Rambukkana
Prof Rambukkana relocated to the Centre for Regenerative Medicine in 2010 from The Rockefeller University New York where he was a faculty member since 2000; his laboratory was funded mainly by NIH (NINDS and NIAID) grants. He obtained his PhD from the University of Amsterdam, The Netherlands, and continued his first postdoctoral training in the Academic Medical Center, University of Amsterdam. He then moved to Rockefeller University for his second postdoctoral training before obtaining his faculty position at Rockefellar University. Prof Rambukkana is also a member of Edinburgh Infectious Diseases and Centre for Discovery Brain Scineces.
Lab in the news
Building on the previous discovery that a bacterial pathogen naturally reprograms adult tissue cells to progenitor cells/stem cells (Masaki et al Cell 2013), we have translated this concept to a naturally infected animal model, nine-banded armadillos. We have shown that the same leprosy bacteria not only reprogram infected animal livers but also grow the liver as a functional organ without causing adverse effects (Cell Rep Medicine 2022). This work made headlines around the world and in was featured in major Science magazines. Below: the commentary from Cell Press and selected articles from over 570 news media websites across the globe:
Video Feature form Brilliant! (opens on YouTube)
BBC News (2022)
BBC Health (2013)
Toshihiro Masaki (Visiting scientist / Honorary fellow )
Vahid Aslanzadeh (Postdoctoral Fellow; in collaboration with Prof Chris Ponting, IGMM)
Keitaro Yamane (Post Doctoral Fellow)
Sam Hess (Visiting Fellow)
- Prof John Glass J. Craig Venter Institute, California, US
- Dr Richard Truman and Dr. R Lahiri National Hansen's Disease Program, US
- Active motif, California, US
- LCScience, Texas, US
- Dr Nicolas Tricaud, INSERM, Institut des Neurosciences de Montpellier, France
- Prof Chris Ponting, Institute of Genetics and Cancer
- Dr Timothy Kendell, IGMM