Cell Regeneration最新文献

This review deals with the human adult cardiomyocyte proliferation as a potential source for heart repair after injury. The mechanism to regain the proliferative capacity of adult cardiomyocytes is a challenge. However, recent studies are promising in showing that the ‘locked’ cell cycle of adult cardiomyocytes could be released through modulation of cell cycle checkpoints. In support of this are the signaling pathways of Notch, Hippo, Wnt, Akt and Jak/Stat that facilitate or inhibit the transition at cell cycle checkpoints. Cyclins and cyclin dependant kinases (CDKs) facilitate this transition which in turn is regulated by inhibitory action of pocket protein e.g. p21, p27 and p57. Transcription factors e.g. E2F, GATA4, TBx20 up regulate Cyclin A, A2, D, E, and CDK4 as promoters of cell cycle and Meis-1 and HIF-1 alpha down regulate cyclin D and E to inhibit the cell cycle. Paracrine factors like Neuregulin-1, IGF-1 and Oncostatin M and Extracellular Matrix proteins like Agrin have been involved in cardiomyocyte proliferation and dedifferentiation processes.

A molecular switch model is proposed that transforms the post mitotic cell into an actively dividing cell. This model shows how the cell cycle is regulated through on- and off switch mechanisms through interaction of transcription factors and signaling pathways with proteins of the cell cycle checkpoints. Signals triggered by injury may activate the right combination of the various pathways that can ‘switch on’ the proliferation signals leading to myocardial regeneration.

Class IIa histone deacetylases (HDACs) are a subfamily of HDACs with important functions in development and adult tissue homeostasis. As opposed to other HDACs, they lack catalytic function and bind transcription factors to recruit transcriptional co-regulators, mostly co-repressors such as nuclear receptor co-repressor (NCoR)/silencing mediator of retinoid and thyroid hormone receptor (SMRT). Class IIa HDACs enhance mouse somatic cell reprogramming to induced pluripotent stem cells (iPSCs) by repressing the function of the pro-mesenchymal transcription factor myocyte enhancer factor 2 (MEF2), which is upregulated during this process. Here, we describe, using HDAC4 and 7 as examples, that class IIa HDACs exhibit nuclear-cytoplasmic trafficking in reprogramming, being mostly cytoplasmic in donor fibroblasts and intermediate cells but translocating to the nucleus in iPSCs. Importantly, over-expressing a mutant form of HDAC4 or 7 that becomes trapped in the nucleus enhances the early phase of reprogramming but is deleterious afterwards. The latter effect is mediated through binding to the exogenous reprogramming factors at pluripotency loci, and the subsequent recruitment of NCoR/SMRT co-repressors. Thus, our findings uncover a context-dependent function of class IIa HDACs in reprogramming and further reinforce the idea that recruitment of co-repressors by the exogenous factors is a major obstacle for reactivating the pluripotency network in this process.

As three decades ago, it was reported that adoptive T cell immunotherapy by infusion of autologous tumor infiltrating lymphocytes (TILs) mediated objective cancer regression in patients with metastatic melanoma. A new era of T cell immunotherapy arose since the improvement and clinical use of anti-CD19 chimeric antigen receptor T cells (CAR-T) for the treatment of refractory and relapsed B lymphocyte leukemia. However, several challenges and difficulties remain on the way to reach generic and effective T cell immunotherapy, including lacking a generic method for generating anti-leukemia-specific T cells from every patient. Here, we summarize the current methods of generating anti-leukemia-specific T cells, and the promising approaches in the future.

Erythrocytes (red blood cells, RBCs) facilitate gas exchange in the lungs and transport oxygen to the tissues. The human body must maintain erythrocyte regeneration to support metabolically active cells and tissues. In many hematological diseases, erythrocyte regeneration is impaired. Researchers have studied erythrocyte regeneration for many years both in vivo and in vitro. In this review, we summarize the sources and main culture methods for generating mature and functional red blood cells in vitro. Hematopoietic stem cells (HSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are classic sources for erythrocyte regeneration. In addition, alternative sources such as immortalized adult human erythroid cell lines and transformed fibroblasts have also been generated and have produced functional red blood cells. The culture systems for erythrocytes differ among laboratories. Researchers hope that improvements in culture techniques may contribute to improved RBC outcomes for blood transfusions, drug delivery and the treatment of hematological diseases.

Single embryonic and adult neural stem cells (NSCs) are characterized by their self-renewal and differentiation potential. Lineage tracing via clonal analysis allows for specific labeling of a single NSC and tracking of its progeny throughout development. Over the past five decades, a plethora of clonal analysis methods have been developed in tandem with integration of chemical, genetic, imaging and sequencing techniques. Applications of these approaches have gained diverse insights into the heterogeneous behavior of NSCs, lineage relationships between cells, molecular regulation of fate specification and ontogeny of complex neural tissues. In this review, we summarize the history and methods of clonal analysis as well as highlight key findings revealed by single-cell lineage tracking of stem cells in developing and adult brains across different animal models.

Long non-coding RNAs (lncRNAs) have crucial roles via tethering with DNA, RNA or protein in diverse biological processes. These lncRNA-mediated interactions enhance gene regulatory networks and modulate a wide range of downstream genes. It has been demonstrated that several lncRNAs act as key regulators in hematopoiesis. This review highlights the roles of lncRNAs in normal hematopoietic development and discusses how lncRNA dysregulation correlates with disease prognoses and phenotypes.

The oncogene c-Jun plays a key role in development and cancer. Yet, its role in cell fate decision remains poorly understood at the molecular level. Here we report that c-Jun confers different fate decisions upon mouse embryonic stem cells (mESCs) in adhesion vs suspension culture. We developed a Tet-on system for temporal induction of c-Jun expression by Doxycycline treatment in mESCs. We show that mESCs carrying the inducible c-Jun TetOn remain pluripotent and grow slowly in suspension when c-Jun expression is induced, whilst when the cells adhere they undergo differentiation and show normal proliferative potential upon c-Jun induction. Our data indicates that c-Jun pushes mESCs in suspension into cell cycle arrest at G1/S, by activating the cell cycle inhibitors Cdkn1a/b and Cdkn2/a/b/c. Despite this cell cycle arrest, they can still re-enter the cell cycle upon transfer to an adhesive surface, and grow into typical mESC colonies, albeit at a lower efficiency. These results demonstrate that mESCs respond to induced c-Jun overexpression differently in suspension or adherent cultures. Our results suggest that cells in suspension may be more resistant to differentiation than when they adhere.

Adult hematopoietic stem cells (HSCs) and progenitors (HPCs) reside in the bone marrow, a highly orchestrated architecture. In the bone marrow, the process of how HSCs exert self-renewal and differentiation is tightly regulated by the surrounding microenvironment, or niche. Recent advances in imaging technologies and numerous knockout or knockin mouse models have greatly improved our understanding of the organization of the bone marrow niche. This niche compartment includes a complex network of mesenchymal stem cells (MSC), osteolineage cells, endothelial cells (arterioles and sinusoids), sympathetic nerves, nonmyelinating Schwann cells and megakaryocytes. In addition, different types of mediators, such as cytokines/chemokines, reactive oxygen species (ROS) and exosomes play a pivotal role in regulating the function of hematopoietic cells. Therefore, the niche components and the hematopoietic system make up an ecological environment that maintains the homeostasis and responds to stress, damage or disease conditions. On the other hand, the niche compartment can become a traitor that can do harm to normal hematopoietic cells under pathological conditions. Studies on the diseased bone marrow niche have only recently begun to appear in the extant literature. In this short review, we discuss the most recent advances regarding the behaviors of normal hematopoietic cells and their niche alterations in hematological malignancies.

Obtaining T cells by reprogramming is one of the major goals in regenerative medicine. Here, we describe a protocol for generating functional T cells from Hoxb5-expressing pro/pre-B cells in vivo. This protocol includes the construction of Hoxb5 recombinant plasmids, retroviral packaging, isolation and viral transduction of pro/pre-B cells, cell transplantation, and phenotypic analysis of induced T cells. The procedure is reproducible and straightforward, providing an approach for generating induced T cells for translational research.

Myocardial infarction leads to the loss of a huge number of cardiomyocytes and the reparatory response to this phenomenon is scar tissue formation, which impairs heart function. Direct reprogramming technology offers an alternative strategy for the generation of functional cardiomyocytes not only in vitro, but also in vivo in the site of injury. Results have demonstrated cardiac tissue regeneration and improvement in heart function after myocardial infarction following local injection of vectors encoding reprogramming transcription factors or miRNAs. This shows the great potential of cardiac reprogramming technology for heart regeneration. However, in addition to cardiomyocytes, other cell types, including endothelial cells and smooth muscle cells are also required to be generated in the damaged area in order to achieve complete cardiac tissue regeneration. To this aim induced proliferative/expandable cardiovascular progenitor cells (iCPCs) appear to be an appropriate cell source, which is capable of differentiation into three cardiovascular lineages both in vitro and in vivo. In this regard, this study goes over in vitro and in vivo cardiac reprogramming technology and specifically deals with cardiac progenitor reprogramming and its potential for heart regeneration.