Pancreatic β cell regeneration induced by clinical and preclinical agents

Diabetes,one of the most common chronic diseases in the modern world,has pancreaticβcell deficiency as a major part of its pathophysiological mechanism.Pancreatic regeneration is a potential therapeutic strategy for the recovery ofβcell loss.However,endocrine islets have limited regenerative capacity,especially in adult humans.Almost all hypoglycemic drugs can protectβcells by inhibitingβcell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress.Several agents,including glucagon-like peptide-1 andγ-aminobutyric acid,have been shown to promoteβcell proliferation,which is considered the main source of the regeneratedβcells in adult rodents,but with less clarity in humans.Pancreatic progenitor cells might exist and be activated under particular circumstances.Artemisinins andγ-aminobutyric acid can induceα-to-βcell conversion,although some disputes exist.Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion,and pharmacological research into FoxO1 inhibition is ongoing.Other cells,including pancreatic acinar cells,can transdifferentiate intoβcells,and clinical and preclinical strategies are currently underway.In this review,we summarize the clinical and preclinical agents used in different approaches forβcell regeneration and make some suggestions regarding future perspectives for clinical application.

Chemical transdifferentiation： closer to regenerative medicine

Cell transdifferentiation, which directly switches one type of differentiated cells into another cell type, is more advantageous than cell reprogramming to generate pluripotent cells and differentiate them into functional cells. This process is crucial in regenerative medicine. However, the cell-converting strategies, which mainly depend on the virus-mediated expression of exogenous genes, have clinical safety concerns. Small molecules with compelling advantages are a potential alternative in manipulating cell fate conversion. In this review, we briefly retrospect the nature of cell transdifferentiation and summarize the current developments in the research of small molecules in promoting cell conversion. Particularly, we focus on the complete chemical compound-induced cell transdifferentiation, which is closer to the clinical translation in cell therapy. Despite these achievements, the mechanisms underpinning chemical transdifferentiation remain largely unknown. More importantly, identifying drugs that induce resident cell conversion in vivo to repair damaged tissue remains to be the end-goal in current regenerative medicine.

Induced neural stem/precursor cells for fundamental studies and potential application in neurodegenerative diseases

Recent research has shown that defined sets of exogenous factors are sufficient to convert rodent and human somatic cells directly into induced neural stem cells or neural precursor cells（iNSCs/iNPCs）.The process of transdifferentiation bypasses the step of a pluripotent state and reduces the risk of tumorigenesis and genetic instability while retaining the self-renewing capacity.This iNSC/iNPC technology has fueled much excitement in regenerative medicine,as these cells can be differentiated into target cells for replacement therapy for neurodegenerative diseases.Patients＇ somatic cell-derived iNSCs/iNPCs have also been proposed to serve as disease models with potential value in both fundamental studies and clinical applications.This review focuses on the mechanisms,techniques,and applications of iNSCs/iNPCs from a series of related studies,as well as further efforts in designing novel strategies using iNSC/iNPC technology and its potential applications in neurodegenerative diseases.

Septation and shortening of outflow tract in embryonic mouse heart involve changes in cardiomyocyte phenotype and α-SMA positive cells in the endocardium

Background Studies on human, rat and chicken embryos have demonstrated that during the period of outflow tract septation, retraction of the distal myocardial margin of the outflow tract from the junction with aortic sac to the level of semilunar valves leads to the shortening of the myocardial tract. However, the mechanism is not clear. So we investigated the mechanism of outflow tract shortening and remodeling and the spatio-temporal distribution pattern of α-SMA positive cells in the outflow tract cushion during septation of the outflow tract in the embryonic mouse heart Methods Serial sections of mouse embryos from embryonic day 9 (ED 9) to embryonic day 16 (ED 16) were stained with monoclonal antibodies against α-SCA, α-SMA, or desmin, while apoptosis was assessed using the terminal deoxyribonucleotidy transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay Results Between ED 11 and ED 12, the cardiomyocytes in the distal portion of the outflow tract were observed losing their myocardial phenotype without going into apoptosis, suggesting that trans-differentiation of cardiomyocytes into the cell components of the free walls of the intrapericardial ascending aorta and pulmonary trunk The accumulation of α-SMA positive cells in the cardiac jelly began on ED 10 and participated in the ridge fusion and septation of the outflow tract Fusion of the distal ridges resulted in the formation of the facing walls of the intrapericardial ascending aorta and pulmonary trunk Fusion of the proximal ridges was accompanied by the accumulation of α-SMA positive cells into a characteristic central whorl, in which cell apoptosis could be observed Subsequent myocardialization resulted in the formation of the partition between the subaortic and subpulmonary vestibules Conclusions The shortening of the embryonic heart outflow tract in mice may result not from apoptosis, but from the trans-differentiation of cells with cardiomyocyte phenotype in the distal portion of the outflow tract into the cell components of the free walls of the intrapericardial ascending aorta and pulmonary trunk The primary roles of α-SMA positive cells in the septation and remodeling of the outflow tract may assure proper fusion of the outflow ridges and form the facing walls of the intrapericardial ascending aorta and pulmonary trunk