Our group studies a pioneering approach from a natural bacterial infection process with cellular reprogramming capacity to address the basic biology of stem cells and cell fate changes in adult tissues. Our recent discovery that human bacterial pathogens like Mycobacterium leprae hijacks the notable plasticity of its adult host tissue niche Schwann cells and reprograms them to stem cell-like cells opens up new premise of investigations not only for developing safer strategies for cell fate change in vivo for tissue regeneration but also for targeting key host-encoded functions of cell reprogramming for combating bacterial infections, particularly the emerging global threat by drug/antibiotic-resistant bacteria.
Our laboratory brings an innovative approach from a natural infection process to address basic biology of progenitor/stem cells and to develop new strategies for reprogramming adult tissue cells to safer progenitor/stem cells or different lineage committed cells in vivo. We study how certain intracellular bacteria, like Mycobacterium leprae as a model, hijack the adult tissue cell plasticity for their advantage. Many years of our studies on 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 reprogram adult Schwann cells to stem cell-like cells (Cell, 2013). Our current studies are focused on how these natural bacterial secrets and ingenuity of cell fate change can be exploited to regenerate injured or diseased tissues. We are also studying how these reprogrammed progenitor/stem cells can be combined with endogenous innate immune cells with natural regenerative properties to promote repair processes in demyelinating neurodegenerative, neuromuscular and liver diseases in varying model systems.
Development of translational applications of our discovery requires that we define the mechanisms and regulations of bacterial-induced host cell reprogramming processes at transcriptional, epigenetic and metabolic levels. With such mechanistic as tools our long-term goals will focus on how the property of adult tissue plasticity can be exploited to generate stem cell-like cells or different lineage committed cells in vivo that could eventually be developed into safer therapeutics in regenerative medicine. To execute our goals we use a multidisciplinary approach with a unique combination of infection biology, stem cell biology, neurobiology and synthetic biology with most up-to-date technologies in cell biology, synthetic genomics, next-generation sequencing and imaging.
We are also applying our new approach of fusion of infection biology and stem cell biology themes to develop new strategies of host-encoded functions of cell reprogramming to combat bacterial infectious diseases. In particular, since drug/antibiotic resistant bacteria are emerging as a global health threat, developing therapeutics that target host-encoded functions required for infections could be potentially effective common approach for combating drug-resistant bacteria. Such interventions would have broad-spectrum efficacy and are less likely to pressure on microbes to emerge drug resistance, a major global concern and challenge.
- 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.
- 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*, 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.
Biography Prof Rambukkana
Prof Rambukkana relocated to the MRC 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 there. Prof Rambukkana is also a member of Edinburgh Infectious Diseases (EID) and Centre for Neuroregeneration (CNR).
Past lab members and their current faculty / scientific positions
- 2001: Yoshihiro Shimoj, Chief Scientist, Bacterial and Parasitic Diseases Research Division, and visiting professor of Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan (Lab publications: PNAS, 1999; PLosOne 2011);
- 2003: Vincent Ng, Assistant professor of Biology, Northern Virginia Community College, Virginia, USA (Lab publications, PNAS 1999; Cell, 2000);
- 2006: Makato Ohinishi, Head, Department of Bacteriology, National Institute of Health, Tokyo, Japan (lab publication: Nature Medicine, 2006);
- 2007: Nikos Tapinos, Assistant professor, Weis Center for Research, Geisinger Clinic, Danville, PA, USA (lab publications: Science, 2002; PNAS, 2005; J. Immunol. 2006; Nature Medicine, 2006);
- 2008: Ryan Raaum, Asst. Professor, Lehman College & The Graduate Center, The City University of New York, USA (Lab publication: Cell 2013);
- 2010: Jinrong Qu, Research Scientist, Memorial Sloan Kettering Cancer Center, New York, USA (Lab publications: Cell 2013; F1000Research 2013; Cell Reprogam 2014);
- 2012: Justyna Cholewa-Waclaw, Research Associate, Adrian Bird’s Laboratory, Center for Cell Biology University of Edinburgh, UK (Lab publications: Cell 2013; Cell Reprogam 2014);
- 2012: Toshihiro Masaki, Professor, Teikyo University, Tokyo, Japan (Lab publications: Cell 2013; F1000Research 2013; Cell Reprogam 2014; Book Chapter 2014).
Lab in the news
The discovery that a human bacterial pathogen naturally reprograms adult tissue cells to stem cells and implications of this finding in regenerative medicine and combatting infectious diseases made headlines in major news portal around the world and in all top ranking journals including its selection to Best of Cell 2013 collection from Cell Press.
- Best of Cell 2013
- Cell Leading Edge - editor comment
- Science news
- Nature news
- Nature Reviews Microbiology - research highlights
- Nature Reviews Molecular Cell Biology - research highlights
- Recommendations Faculty1000, ranked the publication on top of the top ten in the year-end ranking in 2013 with 21 stars under the exceptional category. Also published on the University of Edinburgh News website as well as on the Edinburgh Infectious Diseases website, here and here.