Induced pluripotent stem cells(iPSCs):molecular mechanisms of induction and applications

The induced pluripotent stem cell(iPSC)technology has transformed in vitro research and holds great promise to advance regenerative medicine.iPSCs have the capacity for an almost unlimited expansion,are amenable to genetic engineering,and can be differentiated into most somatic cell types.iPSCs have been widely applied to model human development and diseases,perform drug screening,and develop cell therapies.In this review,we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications.We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs.We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency.Subsequently,we discuss various iPSC-based cellular models,from mono-cultures of a single cell type to complex three-dimensional organoids,and how these models can be applied to elucidate the mechanisms of human development and diseases.We use examples of neurological disorders,coronavirus disease 2019(COVID-19),and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells.We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies.Finally,we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases.

Hypoxia-controlled matrix metalloproteinase-9 hyperexpression promotes behavioral recovery after ischemia

Matrix metalloproteinase-9（MMP-9） plays a beneficial role in the sub-acute phase after ischemic stroke.However,unrestrained MMP-9 may disrupt the blood-brain barrier（BBB）,which has limited its use for the treatment of brain ischemia.In the present study,we constructed lentivirus mediated hypoxiacontrolled MMP-9 expression and explored its role after stroke.Hypoxia response element（HRE）was used to confine MMP-9 expression only to the hypoxic region of mouse brain after 120-min transient middle cerebral artery occlusion.Lentiviruses were injected into the peri-infarct area on day 7 after transient ischemia.We found hyperexpression of exogenous HRE-MMP-9 under the control of hypoxia,and its expression was mainly located in neurons and astrocytes without aggravation of BBB damage compared to the CMV group.Furthermore,mice in the HRE-MMP-9 group showed the best behavioral recovery compared with the normal saline,GFP,and SB-3CT groups.Therefore,hypoxia-controlled MMP-9 hyperexpression during the sub-acute phase of ischemia may provide a novel promising approach of gene therapy for stroke.