Sepsis is a condition where the inflammatory response occurs at such a high level that grave damage is caused to the body, causing millions of deaths each year. Developing therapeutics for sepsis is also considered a graveyard for biotech companies due to the high rate of failures. Although recombinant activated protein C (Xygris) has had some benefit, overall little therapies are available for this condition.
When we discuss stem cell therapy, we normally think about the stem cells regenerating the body, that is, a more chronic process. When we think of sepsis we think of an acute medical event, that must be treated with rapid-acting procedures.
This is why we were so shocked when we read a paper (Nemeth et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009 Jan;15(1):42-9) in the high profile medical journal Nature Medicine, describing the successful use of bone marrow mesenchymal stem cells in the treatment of this condition.
We know that mesenchymal stem cells possess antiinflammatory properties. This, of course, is one of the reasons why we offer stem cell therapy for multiple sclerosis using mesenchymal stem cells. These properties are mediated by the ability of mesenchymal stem cells to secrete factors such as LIF, HLA-G, and IL-10, all of which inhibit inflammation directly or indirectly. However, it was always believed that mesenchymal stem cells mediate their effects in more chronic situations, not in situations where if the problem is not solved within hours the host perishes.
The investigators of the study we will discuss, used a mouse model of sepsis called the “cecal ligation and puncture model” in which the cecum is made to leak and the mouse dies within 24-48 hours if left untreated.
Treatment of mice with mesenchymal stem cells of the same genetic background as the mouse, or of a different genetic background inhibited mortality by about 50% !
More specific examination revealed that administration of mesenchymal stem cells was associated with preservation of liver and kidney function, two organs that are targets of the septic process.
The injection of mesenchymal stem cells was associated with rapid (3 hours !) induction of interleukin 10 production and suppression of the elevated TNF-alpha and interleukin 6 that are characteristic of the septic process.
The next question is whether the injected mesenchymal stem cells actually needed other cells in the body to mediate their effects, or whether they were inducing protection directly on their own. To address this, T cells, B cells, and NK cells were depleted by antibody or genetic means before induction of sepsis. Neither of these depletions affected ability of the mesenchymal stem cells to protect from sepsis. So the next question was whether macrophages were involved.
Depleting macrophages by administration of the chemical clodronate via liposomes resulted abrogation of the beneficial effects of the mesenchymal stem cells. It was found that macrophages produce IL-10 after administration of the mesenchymal stem cells, and it is this IL-10 that protects against sepsis. This was proven since inactivation of circulating IL-10 or blocking of its receptor, took away the protective effects of the administered mesenchymal stem cells.
So how would the mesenchymal stem cells induce production of IL-10 by macrophages? It was found that the mesenchymal stem cells secrete PGE-2, which induces a biological cross-talk with the macrophages resulting in selective IL-10 release.
These data support the overall notion that mesenchymal stem cells are antiinflammatory in general, and specifically can act at the level of the macrophage. Since macrophages are critical for multiple sclerosis progression in the CNS, it will be interesting to evaluate the mechanisms by which protective effects of mesenchymal stem cells are mediated in animal models of multiple sclerosis. Additionally, these data provide yet another interesting method by which mesenchymal stem cells modulate inflammation and immunity.