Importance of the Injury Signal
Warsaw, Poland -
The immune system is activated in response to Danger signals, which evoke various innate molecular pathways that culminate with inflammatory cytokine production and eventual activation of the adaptive immune system. Stem cells circulating in lymphatics have been implicated in recognizing classical danger signals such as toll like receptor agonists which induce their differentiation into dendritic cells. It would make sense that other danger signals exist in the body that induce homing of stem cells to injured areas and in some cases stimulate their differentiation into tissues that are needed.
One example of a signal generated by injured tissue is VEGF which is generated after myocardial infarctions and clinically is associated with mobilization of bone marrow derived stem cells. Another signal is stromal derived factor (SDF-1), which is generated by hypoxic or injured tissue. Normally SDF-1 is produced at a constitutive rate by bone marrow stromal cells. This is why it is possible to inject intravenously hematopoietic stem cells into recipients of bone marrow transplants and the stem cells still home to the bone. In fact, abrogating the CXCR4-SDF-1 interaction by small molecule inhibitors leads to mobilization of stem cells, as was patented by Anormed in patent 7,169,750. Interestingly if one co-cultures stem cells with SDF-1 before administration, the stem cells have a higher potency for cardiac repair.
A very important point in regards to generation of stem cell chemoattractants by damaged tissue is to figure out kinetics and biological relevance. A recent paper (Czarnowska et al. Expression of SDF-1-CXCR4 axis and an anti-remodelling effectiveness of foetal-liver stem cell transplantation in the infarcted rat heart. J Physiol Pharmacol. 2007 Dec;58(4):729-44) tackled this question.
Researchers induced infarcts by cutting off coronary circulation and assessed the infaract area at several timepoints. In some of the rats the investigators implanted fetal liver stem cells at various times post infarct.
Expression of SDF-1 in the peri-infarct zone peaked at day 2 after infarct and returned to normal levels at day 21 as assessed by immunohistochemistry. Cells expressing the SDF-1 receptor CXCR-4 and CD133 (resembling endogenous stem cells) also peaked at day 2. Interestingly if rats were pretreated with the Anormed compound (AMD1300) which abrogates CXCR-4 binding to SDF-1, the number of CXCR-4 positive, CD133 positive cells in the myocardium was decreased. This suggests that SDF-1 being generated by the injured tissue was actually increasing mobilization and homing of stem cells to the injured area.
Administration of the fetal liver stem cells in rats that did not recieve an infarct caused eventual loss and undetectability after 21 days. In contrast, which the stem cells were injected in rats that recieved an infarct, especially when they were injected on day 2 post infarct, the cells survived, caused a further increase in SDF-1 expression and resulted in an improved cardiac profile. Specifically, only the day 2-post infarcted injected cells were capable of inhibiting ventricular wall dilation and also stimulated angiogenesis in the infarct area.
These data suggest the importance of the tissue injury signal in homing of stem cells naturally, but also in determining optimum times for administration of stem cells. The investigation of novel danger signals involved in stem cell activity, such as the TNF alpha family member TWEAK, as well as investigating ways of increasing stem cell chemoattractive ability is bound to provide new research directions and means of increasing efficacy of stem cell therapy.
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Tony Antons said...
Great discussion regarding signals calling in stem cells to damaged tissue (even if you use the term stem cell quite liberally).
I am willing to bet that extracellular matrix degradation products also are involved in producing "danger signals" as you call them, which cause PROGENITORS to home.