Mesenchymal Stem Cells – unwitting partners in Mycobacterial immune evasion

Poor stem cells can’t get a break. I mean, seriously! What is it about mesenchymal (i.e. related to the mesenchyme, a kind of undifferentiated connective tissue) stem cells that makes them so attractive to all manners of deadly bugs to come and take up residence? And by deadly bugs, I mean various shades of Mycobacteria. Let me explain.

Just the other day, science blogger Mo Costandi (of Neurophilosophy fame) commented on a study from the MRC Center for Regenerative Medicine at the University of Edinburgh (Toshihiro Masaki et al.), highlighting a curious and fascinating finding about the leprosy-causing bacterium, Mycobacteria leprae, and stem cells that-are-not-quite.

A quick recap first: Schwann cells, a type of supporting cells found in the peripheral nervous system (PNS), cover (more like, hug) the axons, the elongated fiber-like part of neurons (nerve cells). In case of what are known as myelinated neurons (e.g. sensory and motor neurons), the Schwann cells form a sheath of myelin (a material composed of lipids and proteins) around the axons, whereas in non-myelinated neurons (e.g. the nerve fibers that carry pain sensation), they simply cover the axons with their own cytoplasm. These cells assist in various functions, such as neural impulse conduction, modulation of synaptic activity at the junction of nerves and muscle cells (neuromuscular junction), and nerve regeneration. Ordinarily, Schwann cells are differentiated (i.e. matured, or developmentally committed, into specific roles) cells, but they have the unique ability to ‘dedifferentiate’ (i.e. go back to an immature form), especially when there is nerve injury. The dedifferentiation allows them to restart dividing and thereby aid the regenerative process. Schwann cells also act as scavengers to remove remnants of damaged nerves that can hinder recovery. In short, quite the general factotum of the PNS.

Now, the leprosy bacterium is known to infect Schwann cells preferentially and establish intracellular residence; in addition, it is known to be totally dependent upon the host cell for survival. Masaki and his colleagues discovered a unique phenomenon – subversion of the Schwann cells’ dedifferentiation potential by M. leprae to suit its own nefarious purpose: working from inside, the bacterium is able to switch off the genes that are characteristic of adult Schwann cells, and turn on developmental genes that lead to the regression of these cells to a progenitor/stem cell-like state with migratory and immunomodulatory properties [Cell, 152(1-2): 51-67, 2013]. In other words, the bacteria reprograms the genetics of the Schwann cells to convert them to a type of stem cells which can, then, (a) re-differentiate into mesenchymal tissues, such as skeletal and smooth muscle cells laden with the bacteria, and (b) migrate to the general circulation – with the bacteria enjoying the merry ride from inside – and pass the bacteria on to macrophages, which form granulomas with other macrophages and contribute to spreading the infection. Interesting, huh? An elaborate Trojan Horse (Trojan Stem Cell?) strategy, or perhaps a Decepticon transforming ordinary, everyday gadgets to weapon bots – take your pick!

Now, M. leprae‘s more dastardly cousin, M. tuberculosis (Mtb) has joined the fray to abuse stem cells. Tuberculosis is, indeed, a special case; it’s a bug with a cunning plan. It does generate a robust cell-mediated immune (CMI) response in the host body, involving T-lymphocytes and macrophages, and yet, Mtb manages to evade being killed, and persists, often for years, within the body following the initial infection. In 2010, a group of Indian researchers from two New Delhi-based research institutions (the International Center for Genetic Engineering and Biotechnology, and my alma mater, All India Institute of Medical Sciences) elucidated a part of the mechanism which enables Mtb to hide in plain sight. Guess what Mtb Shanghais in order to achieve that? Stem cells!

In this study, Raghuvanshi and her colleagues demonstrated a profound inhibition of T-cell proliferation responses during Mtb infection [Proceedings of the National Academies of Sciences of USA, 107(50): 21653-8, 2010]; after systematically eliminating the possible causes for this anergy, they discovered that the bug was directly responsible. How? It appears that the infecting Mtb can recruit (bring to the site of infection) migratory mesenchymal stem cells, which, in turn, inhibit T-cell responses by elaborating various chemical substances that stop the division of T-cells (‘cell cycle arrest’) and cause them to commit suicide (‘induction of apoptosis’). They also induce a different class of T-cells, called regulatory T-cells or “Treg”s, whose purpose in life is to dampen the enthusiasm of immune-warrior T-cells.

Continuing that trend, a collaborative study – between Stanford University, Cambridge, MA-based Forsyth Institute, a Canadian hospital, and three prominent institutions from the North-Eastern part of India – recently found that one of the main mechanisms of long-term persistence and survival of Mtb in the host body involve a certain mesenchymal sub-population of – again – bone marrow-derived stem cells (BM-MSCs). Das and his colleagues report that Mtb, in a non-replicating albeit viable form, can hide inside these BM-MSCs, remaining dormant for years [Science Translational Medicine, 5(170): 170ra13, 2013]. These mesenchymal stem cells offer an attractive niche for the Mtb to hide in; there is evidence of recruitment of stem cells at the site of infection in the tissues, and these cells are self-renewing and lead a relatively quiescent existence away from the hubbub of immune activities (i.e., what is known as ‘immune-privileged niches’ – where Tregs keep the immune unrest low). In addition, they have mechanisms to keep many drugs out, and so it’s no wonder, that in an infected person, when the anti-tubercular therapy makes life hard for Mtb, these mesenchymal stem cells are often where the bug comes to hide out. In vitro experiments show that while inside these stem cells, Mtb can even multiply, and retain their viability. Here, then, is a potential reservoir for viable Mtb which can bounce back and reinfect the same hosts many years later. The authors extend the possibility that these cells may be offering similar niches to other potential pathogens also!

Schema of MTb dormancy

Rectangles with solid red border: tentative mechanisms

A silver lining in all these findings? Newer therapeutic options – which may be able to carry out targeted strikes on these stem cells, ensuring destruction of the bug harbored within, and minimizing collateral damage of other cell types throughout the body.