细胞直接重编程:从一种终末分化细胞直接重编程为另一种终末分化细胞

细胞的直接重编程是指将一种终末分化细胞直接转变为另一种终末分化细胞,这一转变不经过诱导多能干细胞阶段和去分化、再分化等过程。最近的一系列研究结果已经证明了这一研究方法的可行性,这些研究进展不仅为重编程的分子机制研究提供了新视角,也为加速重编程细胞的临床应用带来了希望。本文综述了将成纤维细胞直接重编程为神经细胞、肝细胞、心肌细胞及造血细胞的研究进展,探讨了这一研究方法存在的问题以及将来在该领域的研究方向。     

Efficient generation of iPS cells from skeletal muscle stem cells

Reprogramming of somatic cells into inducible pluripotent stem cells generally occurs at low efficiency, although what limits reprogramming of particular cell types is poorly understood. Recent data suggest that the differentiation status of the cell targeted for reprogramming may influence its susceptibility to reprogramming as well as the differentiation potential of the induced pluripotent stem (iPS) cells that are derived from it. To assess directly the influence of lineage commitment on iPS cell derivation and differentiation, we evaluated reprogramming in adult stem cell and mature cell populations residing in skeletal muscle. Our data using clonal assays and a second-generation inducible reprogramming system indicate that stem cells found in mouse muscle, including resident satellite cells and mesenchymal progenitors, reprogram with significantly greater efficiency than their more differentiated daughters (myoblasts and fibroblasts). However, in contrast to previous reports, we find no evidence of biased differentiation potential among iPS cells derived from myogenically committed cells. These data support the notion that adult stem cells reprogram more efficiently than terminally differentiated cells, and argue against the suggestion that "epigenetic memory" significantly influences the differentiation potential of iPS cells derived from distinct somatic cell lineages in skeletal muscle.     

Application of reprogrammed patient cells to investigate the etiology of neurological and psychiatric disorders

Cellular reprogramming allows for the de novo generation of human neurons and glial cells from patients with neurological and psychiatric disorders.Crucially,this technology preserves the genome of the...     

细胞命运转变——谱系重编程技术研究进展

体细胞核移植和诱导多能干细胞技术表明已分化的体细胞可以转变命运。最近的研究再一次验证了成熟体细胞可以通过外源转录因子的导入,直接重编程为其他类型的体细胞或祖细胞。这种重编程技术称为谱系重编程(Lineage reprogramming)。这项技术不仅在再生医学领域具有广阔的应用前景,而且在动物生物技术中也应用广泛。它不但避免了伦理争议,还提供了便利的重编程方法,同时也为基因表达调控的研究提供了重要的手段。文章从谱系重编程的方式、谱系重编程的特点及应用前景等3个方面进行了综述,旨在对相关领域的研究人员起到借鉴作用。     

Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds

Recently, we reported a chemical approach to generate pluripotent stem cells from mouse fibroblasts. However, whether chemically induced pluripotent stem cells (CiPSCs) can be derived from other cell types remains to be demonstrated. Here, using lineage tracing, we first verify the generation of CiPSCs from fibroblasts. Next, we demonstrate that neural stem cells (NSCs) from the ectoderm and small intestinal epithelial cells (IECs) from the endoderm can be chemically reprogrammed into pluripotent stem cells. CiPSCs derived from NSCs and IECs resemble mouse embryonic stem cells in proliferation rate, global gene expression profile, epigenetic status, self-renewal and differentiation capacity, and germline transmission competency. Interestingly, the pluripotency gene Sall4 is expressed at the initial stage in the chemical reprogramming process from different cell types, and the same core small molecules are required for the reprogramming, suggesting conservation in the molecular mechanism underlying chemical reprogramming from these diverse cell types. Our analysis also shows that the use of these small molecules should be fine-tuned to meet the requirement of reprogramming from different cell types. Together, these findings demonstrate that full chemical reprogramming approach can be applied in cells of different tissue origins and suggest that chemical reprogramming is a promising strategy with the potential to be extended to more initial types.     

Mouse embryonic stem (ES) cell lines established from neuronal cell-derived cloned blastocysts

We have established mouse embryonic stem (ES) cell lines from blastocysts derived by transfer of nuclei of fetal neuronal cells. These neuronal cell-derived embryonic cell lines had properties that characterize them as ES cells, including typical cell markers and alkaline phosphatase activity. Moreover, the cells had a normal karyotype and were pluripotent, as they were capable of differentiating into all three germ layers. Although they were derived from neuronal donor nuclei, the cells no longer expressed neuronal markers; however, they were capable of differentiating into cells with neuronal characteristics. These results suggest that the clone-derived cells have fully acquired an ES cell character. Thus, ES cells can be derived from embryos resulting from nuclear transfer, which results in reprogramming of the genetic information and acquisition of pluripotency. ES cells established from somatic cell-derived blastocysts could be useful not only as research tools for studying reprogramming but also as models for cell-based transplantation therapy.     

Induced cardiac progenitor cells repopulate decellularized mouse heart scaffolds and differentiate to generate cardiac tissue

Native myocardium has limited regenerative potential post injury. Advances in lineage reprogramming have provided promising cellular sources for regenerative medicine in addition to research applications. Recently we have shown that adult mouse fibroblasts can be reprogrammed to expandable, multipotent, induced cardiac progenitor cells (iCPCs) by employing forced expression of five cardiac factors along with activation of canonical Wnt and JAK/STAT signaling. Here we aim to further characterize iCPCs by highlighting their safety, ease of attainability, and functionality within a three-dimensional cardiac extracellular matrix scaffold. Specifically, iCPCs did not form teratomas in contrast to embryonic stem cells when injected into immunodeficient mice. iCPC reprogramming was achieved in wild type mouse fibroblasts without requiring a cardiac-specific reporter, solely utilizing morphological changes to identify, clonally isolate, and expand iCPCs, thus increasing the versatility of this technology. iCPCs also show the ability to repopulate decellularized native heart scaffolds and differentiated into organized structures containing cardiomyocytes, smooth muscle, and endothelial cells. Optical mapping of recellularized scaffolds shows field-stimulated calcium transients that propagate across islands of reconstituted tissue and bipolar local stimulation demonstrates cell-cell coupling within scaffolds. Overall, iCPCs provide a readily attainable, scalable, safe, and functional cell source for a variety of application including drug discovery, disease modeling, and regenerative therapy.