Stem/progenitor cells in liver injury repair and regeneration

Morbidity and mortality from cirrhosis is increasing rapidly in the world. Currently, orthotopic liver transplantation is the only definitive therapeutic option. However, its clinical use is limited, because of poor long‐term graft survival, donor organ shortage and high costs associated with the procedure. Stem cell replacement strategies are therefore being investigated as an attractive alternative approach to liver repair and regeneration. In this review we discuss recent preclinical and clinical investigations that explore the therapeutic potential of stem cells in repair of liver injuries. Several types of stem cells. including embryonic stem cells, haematopoietic stem cells and mesenchymal stem cells, can be induced to differentiate into hepatocyte‐like cells by defined culture conditions in vitro. Stem cell transplantation has been shown to significantly improve liver function and increase animal survival in experimentally‐induced liver‐injury models. Moreover, several pilot clinical studies have reported encouraging therapeutic effects in patients treated with stem cells. Although there remain many unresolved issues, the available data support the notion that stem cell technology may lead to the development of effective clinical modalities for human liver diseases.     

Human hair follicle pluripotent stem (hfPS) cells promote regeneration of peripheral‐nerve injury: An advantageous alternative to ES and iPS cells

The optimal source of stem cells for regenerative medicine is a major question. Embryonic stem (ES) cells have shown promise for pluripotency but have ethical issues and potential to form teratomas. Pluripotent stem cells have been produced from skin cells by either viral‐, plasmid‐ or transposon‐mediated gene transfer. These stem cells have been termed induced pluripotent stem cells or iPS cells. iPS cells may also have malignant potential and are inefficiently produced. Embryonic stem cells may not be suited for individualized therapy, since they can undergo immunologic rejection. To address these fundamental problems, our group is developing hair follicle pluripotent stem (hfPS) cells. Our previous studies have shown that mouse hfPS cells can differentiate to neurons, glial cells in vitro, and other cell types, and can promote nerve and spinal cord regeneration in vivo. hfPS cells are located above the hair follicle bulge in what we have termed the hfPS cell area (hfPSA) and are nestin positive and keratin 15 (K‐15) negative. Human hfPS cells can also differentiate into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. In the present study, human hfPS cells were transplanted in the severed sciatic nerve of the mouse where they differentiated into glial fibrillary‐acidic‐protein (GFAP)‐positive Schwann cells and promoted the recovery of pre‐existing axons, leading to nerve generation. The regenerated nerve recovered function and, upon electrical stimulation, contracted the gastrocnemius muscle. The hfPS cells can be readily isolated from the human scalp, thereby providing an accessible, autologous and safe source of stem cells for regenerative medicine that have important advantages over ES or iPS cells. J. Cell. Biochem. 107: 1016–1020, 2009. © 2009 Wiley‐Liss, Inc.     

Intratumoral interferon-α gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation

One of the major challenges in the treatment of solid cancers by allogenic hematopoietic stem cell transfer (alloHSCT) is the specific enhancement of antitumor immunity. Interferon (IFN) is a cytokine with pleiotropic biological functions including an immunomoduration, and our preclinical studies have shown that an intratumoral IFN-α gene transfer induced strong local tumor control and systemic tumor-specific immunity. In the present study, we examined whether the IFN-α gene transfer could enhance recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. First, when a mouse IFN-α adenovirus vector (Ad-mIFN) was injected into subcutaneous xenografts of syngeneic renal and colon cancer cells, tumor growth was significantly suppressed in a dose-dependent manner. A significant tumor cell death and infiltration of immune cells was recognized in the Ad-mIFN-injected tumors, and the dendrtic cells isolated from the tumors showed a strong Th1-oriented response. The antitumor effect of Ad-mIFN was then examined in a murine model of minor histocompatibility antigen-mismatched alloHSCT. The intratumoral IFN-α gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors which did not receive the vector injection. A cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to IFN-α. Graft-versus-host disease was not exacerbated serologically or clinically in the mice treated with IFN-α. This combination strategy deserves evaluation in future clinical trials for human solid cancers.     

黑杨胚抢救技术体系优化

采用组织培养技术进行黑杨胚抢救和比较不同黑杨派树种杂交组合以及不同胚抢救时间的结果表明黑杨胚抢救的最佳时间范围为授粉后30-35d。已长有3支以上须根的胚培苗进行移栽时保持的温度为20-25℃,湿度为70％左右,3d可成活,1周即可完全适应外界环境。     

诱导多能干细胞在心血管疾病研究和治疗中的应用

诱导多能干细胞（induced pluripotent stem cells,iPS细胞）不仅具有与胚胎干细胞（embryonic stem cell,ESC）相似的各项特性,相对于ESC,iPS细胞,尤其患者特异性iPS细胞还具有来源方便、不存在免疫排斥和伦理问题以及可以保留特定个体基因型等优点,为再生医学提供了可能的细胞来源。该文主要从心血管药物的筛选、疾病模型的建立、iPS细胞应用于心脏移植研究等方面入手,探讨了iPS细胞在心血管疾病研究和治疗中的现状和未来。     

Transplantation and cultivation of fragments of coral colonies of various scleractinian species on a reef in Vietnam

Six coral species of the genus Acropora and two species of the genus Porites were studied during experiments on cultivation of reef-building scleractinian corals. The research has established species-specific factors and others affecting regeneration of fragments and growth of new colonies in these coral species. The accretion of donor fragments and new branches averaged from 40 to 160 mm per year, depending on the coral species, colony size, and season of transplantation. An average monthly accretion of medium and larger transplants and growth of new branches were 1.2–1.3 times higher at spring cultivation than at autumn transplanting. When transplanted, coral fragments of medium and larger sizes survived well and showed higher growth rates in all species studied. These transplants developed the highest number of new branches, and their buds and formed the largest colonies. Prolongation of the cultivation time from 1 to 1.5 years caused a 1.2–1.4 fold accretion of transplants.     

In vitro expansion of long-term repopulating hematopoietic stem cells in the presence of immobilized Jagged-1 and early acting cytokines

There is an increasing body of evidence that suggests that genes involved in cell fate decisions and pattern formation during development also play a key role in the continuous cell fate decisions made by adult tissue stem cells. Here we show that prolonged in vitro culture (14 days) of murine bone marrow lineage negative cells in medium supplemented with three early acting cytokines (stem cell factor, Flk-2/Flt-3 ligand, thrombopoietin) and with immobilized Notch ligand, Jagged-1, resulted in robust expansion of serially transplantable hematopoietic stem cells with long-term repopulating ability. We found that the absolute number of marrow cells was increased approximately 8 to 14-fold in all cultures containing recombinant growth factors. However, the frequency of high quality stem cells was markedly reduced at the same time, except in cultures containing growth factors and Jagged-1-coated Sepharose-4B beads. The absolute number of hematopoietic cells with long-term repopulating ability was increased approximately 10 to 20-fold in the presence of multivalent Notch ligand. These results support a role for combinatorial effects by Notch and cytokine-induced signaling pathways in regulating hematopoietic stem cell fate and to a potential role for Notch ligand in increasing cell numbers in clinical stem cell transplantation.     

Protective effect of carbon monoxide in transplantation

During the last decades due to the development of new immunosuppressive agents and improvements in organ preservation methods, surgical techniques, and postoperative care, organ transplantation has become an ultimate therapeutic option for irreversible organ failure. Early graft survival has significantly improved; however, the long-term outcome remains unsatisfactory. Multiple factors, both immunogenic and non-immunogenic etiologies, are involved in the deterioration of the allografts, and the recent use of expanded criteria donors to overcome the organ shortage may also contribute to the graft losses. Carbon monoxide (CO) is commonly viewed as a poison in high concentrations due to its ability to interfere with oxygen delivery. However, CO is endogenously produced in the body as a byproduct of heme degradation by the heme oxygenase (HO) and has recently received notable attention as a gaseous regulatory molecule. In fact, an augmentation of endogenous CO by induction of HO-1 or exogenously added CO is known to have potent cytoprotective effects in various disease models. Several recent reports have demonstrated that CO provides potent cytoprotective effects in the field of organ and cell transplantation. CO is able to prevent ischemia/reperfusion injury, allograft rejection, and xenograft rejection via its anti-inflammatory, anti-apoptotic and anti-proliferation effects, suggesting that CO might be a valuable therapeutic option in the field of transplantation. Based on the recent advancement of our understanding of CO as a new therapeutic molecule, this review attempts to summarize the functional roles as well as biological and molecular mechanisms of CO in transplantation and discusses potential CO application to the clinical transplant setting.     

Studies on the Developmental Potentiality of Cultured Cell Nuclei of Fish

By means of the serial nuclear transplantation technique, the authors obtained a nuclear transplant fish from subcultured cell originated from the blastula cells of the crucian carp (Carassius auratus Linnaeus). This nuclear transplant fish survived for three years, but its sexual glands were undifferentiated. The authors have also obtained a sexually mature adult fish from short-term cultured kidney cell nucleus of an adult crucian carp.Results of the experiment implied that the subcultured cell nuclei of fish blastula cells and the specialized somatic cell nuclei of adult fish still retained their developmental totipotency, and thus, it indicated that there is a possibility of fish somatic cell breeding through the use of nuclear transplantation.