Anura Rambukkana Research Group
Adult tissue cell plasticity, reprogramming, fate change and regeneration
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.
Aims and areas of interest
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.
Hess S, Rambukkana A. 2015. Bacterial-induced cell reprogramming: 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.
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
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. In the F1000 rankings the paper was top of the top ten in the year-end ranking in 2013 with 21 stars under the exceptional category.
Samuel Hess (Postdoctoral Fellow)
Toshihiro Masaki (Visiting scientist / Honorary fellow )
Vahid Aslanzadeh (Postdoctoral Fellow; in collaboration with Prof Chris Ponting, IGMM)
Keitaro Yamane (Post Doctoral Fellow)