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Improving Organ Function after Injury by Targeting Stem Cells?

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Review of “Perivascular Gli1+ Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis” from Cell Stem Cell by Stuart P. Atkinson

The ability of mesenchymal stem cells (MSCs) to modulate tissue injury and repair have promoted their investigation in a multitude of clinical trials [1]. However, the little that we understand about MSCs comes from in vitro observations of cultured MSCs due to the lack of a reliable cell marker in vivo. One potentially interesting candidate marker is Gli1; a member of the Kruppel zinc finger proteins activated by the sonic hedgehog signal transduction cascade which regulates stem cell proliferation. Previous studies found Gli1 to mark perivascular MSC-like cells in the mouse incisor [2], and now the group of Benjamin D. Humphreys (Harvard Medical School, Boston, USA) have identified Gli1+ perivascular MSC-like cells as a major cellular origin of organ fibrosis after injury in mice [3]. They hope that their research may provide targets for therapeutic intervention to prevent fibrosis and in doing so inhibit subsequent organ dysfunction in humans.

The researchers began this study by creating and analyzing a genetic cross which marked all Gli1+ cells. This demonstrated that Gli+ cells lay adjacent to endothelial cells (ECs) in microvascular capillaries and large arteries, and that they co-expressed the mesenchymal marker PDGFR. Gli1+ cells displayed mesenchymal like tri-potent differentiation capacity in vitro and expressed other mesenchymal markers (3G5, Nestin, and PDGFRa), but not the EC marker CD31 or the hematopoietic marker CD45. More detailed analysis found that Gli1+/ PDGFR+ cells represented only a small fraction of total PDGFR+ cells and these demonstrated a much higher clonogenic potential with larger colony formation. Indeed, Gli1 induction through adding Shh led to increased colony number, while adding small molecule antagonist GANT61 decreased Gli1 protein levels and also decreased colony forming capacity.

A prevailing theory is that organ injury leads to activation of perivascular MSCs to support tissue regeneration [1], and so the authors used cell tracking experiments to assess the impact of Gli1+ cells after injury to major organs. Studies of the kidney, heart, liver and lungs all demonstrated a dramatic increase in Gli1+ cells after injury. Furthermore, these cells acquired the expression of -SMA, indicative of cells differentiating into myofibroblasts, the main cell type contributing to fibrosis. Myofibroblastic differentiation also impaired the Gli1+ cell-EC cell association, thereby inhibiting angiogenic potential. The authors also found, through bone marrow transplant and parabiosis experimentation, that only resident Gli1+ cells differentiated in myofibroblasts, and not bone-marrow derived/circulating MSCs as previously thought [4].

The authors finished their study with the now obvious question: can we inhibit injury associated fibrosis and thereby improve organ function? Excitingly, the group demonstrated that loss of Gli1+ cells mediated a 50% decrease in kidney fibrosis, and reduced fibrosis in the heart by such an amount as to rescue heart failure by preserving left ventricular ejection fraction.

This exciting study not only illustrates the important role for perivascular MSCs in organ repair, but also indicates that the specific targeting of a small cell population marked with Gli1 has the potential to inhibit a loss in organ functionality. Further knowledge of the signaling pathways which control the myofibroblastic switch after injury in Gli1 cells may uncover a means to inhibit fibrosis to a level where organ remain functional after repair.

References

  1. Caplan AI and Correa D The MSC: an injury drugstore. Cell Stem Cell 2011;9:11-15.
  2. Zhao H, Feng J, Seidel K, et al. Secretion of shh by a neurovascular bundle niche supports mesenchymal stem cell homeostasis in the adult mouse incisor. Cell Stem Cell 2014;14:160-173.
  3. Kramann R, Schneider RK, DiRocco DP, et al. Perivascular Gli1 Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis. Cell Stem Cell 2014. In Press
  4. LeBleu VS, Taduri G, O'Connell J, et al. Origin and function of myofibroblasts in kidney fibrosis. Nature medicine 2013;19:1047-1053.