Novel strategies of regenerative medicine using chemical compounds.

Many diseases and/or physical defects due to injury result in the loss of specialized cells within organ systems and lead to organ system dysfunction. The ultimate goal of cell-based therapies is to regenerate and restore normal function. Populations of embryonic, fetal, adult stem cells and inducible pluripotent stem cells generated by reprogramming of adult cells show promise for the treatment of a variety of diseases. In addition, the recent advancements in adult stem cell biology in both normal and pathological conditions have led to the identification of some intrinsic and extrinsic factors that govern the decision between self renewal versus differentiation of tissue-resident adult stem cells. This is of primary importance for the design of an approach of stem cell-based therapy focused on their in vivo modulation by conventional chemical and biological therapeutics capable to stimulate endogenous cell regeneration. Such therapeutics can act in vivo to promote cell survival, proliferation, differentiation, reprogramming and homing of stem cells or can modulate their niches. In this review, we will highlight the burst of recent literature on novel perspectives of regenerative medicine and their possible clinical applications.

Immunomodulatory effects of BXL-01-0029, a less hypercalcemic vitamin D analogue, in human cardiomyocytes and T cells.

Current immunosuppressive protocols have reduced rejection occurrence in heart transplantation; nevertheless, management of heart transplant recipients is accompanied by major adverse effects, due to drug doses close to toxic range. In allograft rejection, characterized by T-helper 1 (Th1) cell-mediated response, the CXCL10-CXCR3 axis plays a pivotal role in triggering a self-promoting inflammatory loop. Indeed, CXCL10 intragraft production, required for initiation and development of graft failure, supports organ infiltration by Th1 cells. Thus, targeting the CXCL10-CXCR3 axis while avoiding generalized immunosuppression, may be of therapeutic significance. Based on preclinical evidence for immunoregulatory properties of vitamin D receptor agonists, we propose that a less hypercalcemic vitamin D analogue, BXL-01-0029, might have the potential to contribute to rejection management. We investigated the effect of BXL-01-0029 on CXCL10 secretion induced by proinflammatory stimuli, both in human isolated cardiomyocytes (Hfcm) and purified CD4+ T cells. Mycophenolic acid (MPA), the active agent of mycophenolate mofetil, was used for comparison. BXL-01-0029 inhibited IFNgamma and TNFalpha-induced CXCL10 secretion by Hfcm more potently than MPA, impairing cytokine synergy and pathways. BXL-01-0029 reduced also CXCL10 protein secretion and gene expression by CD4+ T cells. Furthermore, BXL-01-0029 did not exert any toxic effect onto both cell types, suggesting its possible use as a dose-reducing agent for conventional immunosuppressive drugs in clinical transplantation.

[The role of endothelial progenitor cells in renal disease]. / Ruolo dei progenitori endoteliali nelle malattie renali.

Recent evidence suggests that injury to the renal vasculature may play an important role in the pathogenesis of both chronic and acute ischemic kidney injury. Early alterations in peritubular capillary blood flow during reperfusion have been documented and associated with loss of normal endothelial cell function. In addition, ischemia induces alterations in endothelial cells that may promote inflammation and procoagulant activity, thus contributing to vascular congestion. Reduction of the microvasculature density increases hypoxia-mediated fibrosis and alters proper hemodynamics, which may lead to hypertension. This may play a critical role in the progression of chronic kidney disease following initial recovery from ischemia/reperfusion-induced acute kidney injury. The turnover and replacement of endothelial cells is therefore an important mechanism in the maintenance of vascular integrity also in the kidney. It is becoming clear that impaired vascular repair mechanisms as a result of a reduced number and/or impaired function of endothelial progenitor cells may contribute to renal disease. Moreover, investigators have begun to identify potential mechanisms responsible for the loss of function of endothelial progenitors in renal disease. In allografts, persistent injury results in excessive turnover of graft vascular endothelial cells. Moreover, chronic damage elicits a response that is associated with the recruitment of both leukocytes and endothelial progenitors, facilitating an overlapping process of inflammation and angiogenesis. In conclusion, angiogenesis and endothelial cell turnover play a pivotal role in renal disease and allograft rejection. Manipulation of these processes might have important implications for the development of novel therapeutic strategies in the near future.