Stem cell transplantation in the treatment of systemic lupus erythematosus: reports from China

回顾近10年国内期刊上关于干细胞移植治疗系统性红斑狼疮的报道,绝大部分为自体外周造血干细胞移植,异体骨髓间充质干细胞移植仅有2例报道,尚无自体骨髓间充质干细胞移植治疗系统性红斑狼疮的报道.     

皮肤间充质干细胞在促进皮肤愈合中的作用

间充质干细胞(mesenchymal stem cells,MSCs)是当前干细胞研究的热点之一。目前,皮肤愈合正逐渐受到重视。现有的研究认为骨髓间充质干细胞(BM-MSCs)能从多个方面促进皮肤愈合,如促进表皮生长、促进真皮成纤维细胞的增生等。皮肤间充质干细胞(SMSCs)和BM-MSCs均为MSCs,具有很多的相似性,且SMSCs较BM-MSCs更容易得到。所以可从目前对BM-MSCs的研究预测到SMSCs在皮肤创伤愈合中的研究前景,且将来很可能会替代BM-MSCs。     

间充质人脐带血干细胞治疗丘疹性黏蛋白病1例

目的 观察间充质人脐带血干细胞治疗丘疹性黏蛋白病的疗效.方法 予患者间充质人脐带血干细胞25mL静脉滴注,1次/周,共6周治疗.结果 经6周治疗后,患者皮损有明显改善,面部结节变平、变软,躯干部皮肤变软,可捏起,无新发皮损.结论 间充质人脐带血干细胞治疗罕见疾病——丘疹性黏蛋白病,有一定疗效,值得在临床中继续观察.     

干细胞移植治疗与重要脏器功能的修复与重建

干细胞（stem cells, SCs）是具有自我更新、高度增殖和多向分化潜能的细胞，通过分裂维持自身细胞群的大小，同时又可分化成为各种不同的组织细胞，从而构成机体各种复杂的组织器官[1]。根据干细胞所处的发育阶段分为：胚胎干细胞（embryonic stem cells，ESCs）；成体干细胞（somatic stem cells，SSCs）。人体几乎所有组织都存在经历相当程度的分化SSCs，但在特定条件下，一种组织的SSCs可以“横向分化”成其他组织的功能细胞，如间充质干细胞（mesenchymal stem cells, MSCs）可以分化成神经、肌肉、软骨和骨等多种细胞[2]。MSCs属于中胚层的一类多能干细胞，主要存在于结缔组织和器官间质中，以骨髓组织中含量最为丰富，且主要来源于骨髓，又称为骨髓间充质干细胞（bone marrow mesenchymal stem cells, BMSCs）。Friedenstein等[3]于1976年首先分离BMSCs，研究证实BMSCs具有强大的增殖能力和多向分化潜能、免疫调节及免疫重建功能，并且来源方便，易于分离、培养、扩增和纯化，经多次传代扩增后仍具有干细胞特性，不存在免疫排斥。因此，BMSCs可能成为细胞移植和基因治疗的理想材料，目前国内外正在探索用于神经系统疾病及多领域多学科难治性疾病的治疗，并已取得了重大突破性进展[4-6]。我国MSCs的研究发展极为迅速，某些核心技术已占国际领先地位，2001年国家批准建立“国家干细胞工程产品产业化基地”，2002年4月在天津建立“国家干细胞工程技术研究中心”。     

CT引导行骨髓源性间充质干细胞术的配合与护理

通过不断的创新研究,武警总医院神经干细胞移植科在治疗脊髓损伤后遗症方面除延用传统的"腰椎穿刺干细胞移植"和"脊髓探查+神经干细胞移植"的手术方法,采用了CT引导下行骨髓源性间充质干细胞移植,它是一种新的移植方法,具有创伤小、定位准确、疗效好的优点[1],现将本科脊髓损伤后遗症患者CT引导下行骨髓源性间充质干细胞术围手术期的护理报道如下.     

脐带间质干细胞和脐血干细胞治疗难治性天疱疮一例

天疱疮是一种累及皮肤和黏膜的有潜在致命性的以水疱和溃疡为主要表现的自身免疫性疾病,系统应用糖皮质激素是其主要治疗方法,各种免疫抑制剂是其辅助治疗手段,随着对天疱疮发病机制研究的深入,各种新的治疗方法不断涌现,为探讨脐带间充质干细胞移植治疗天疱疮的可能性,我们应用脐带间充质干细胞移植治疗1例难治性天疱疮患者,取得了满意的近期效果,为天疱疮的治疗开辟了新的途径。     

间充质干细胞移植治疗系统性红斑狼疮的研究进展

间充质干细胞是来源于发育早期中胚层的成体干细胞,具有高度增殖、自我更新能力、多向分化潜能、损伤组织修复功能和免疫抑制能力。该文综述间充质干细胞,主要是脐带间充质干细胞和骨髓间充质干细胞用于治疗系统性红斑狼疮的研究进展,并提示间充质干细胞移植在未来的细胞治疗中是非常有前景的一种方法。     

间充质干细胞诱导分化为皮肤附属器的研究进展

临床患者由于外伤、严重烧伤及瘢痕切除等导致大面积皮肤缺损时面临自体皮肤移植供体不足的难题,且组织工程皮肤因皮肤附属器的缺失,导致汗液无法排出、毛发丧失等使患者生存质量和心理健康受到严重影响。随着再生医学的发展,间充质干细胞因其来源丰富、低免疫原性、体外扩增能力强及具有多向分化潜能的优势逐渐成为组织工程皮肤种子细胞来源的研究热点。本文就MSCs向毛囊、汗腺、皮脂腺等皮肤附属器的诱导分化作一综述。     

自体骨髓干细胞移植配合中药治疗糖尿病足溃疡的疗效及其与血清VEGF水平关系的研究

目的探讨自体骨髓干细胞移植与中药合用治疗糖尿病足的疗效及其与血清血管内皮生长因子(VEGF)水平的关系。方法选择80例因慢性下肢缺血引起糖尿病足溃疡患者,分为常规治疗组(A组),中药治疗组(B组),自体骨髓干细胞移植治疗组(C组),自体骨髓干细胞移植与中药合用治疗组(D组),每组各20例,各40条患肢。治疗3个月,观察各项指标,对疗效及其与血清VEGF水平关系进行评估。结果①治疗后1周,C、D两组肢体疼痛、患肢冷感、皮肤温度、血清VEGF水平与治疗前比较差异有统计学意义(P0.05);血清VEGF水平与肢体疼痛、患肢冷感、皮肤温度之间存在相关性(P0.05)。治疗后1个月、3个月血清VEGF水平与治疗前比较差异无统计学意义(P0.05)。②治疗后1周C、D两组肢体疼痛、患肢冷感、皮肤温度、血清VEGF水平与A、B组比较差异有统计学意义(P0.05)。③治疗后3个月,C、D两组各项临床观察指标与治疗前比较差异均有统计学意义(P0.05);D组除踝臂指数外其他各项临床观察指标与C组比较差异均有统计学意义(P0.05)。④自体骨髓干细胞移植与中药合用可以提高糖尿病足的疗效,存在交互作用(P0.05)。结论自体骨髓干细胞移植技术与伍用中药治疗慢性下肢缺血引起糖尿病足溃疡可以提高疗效,不会导致由于血清VEGF水平长期增高引起的副作用。     

间充质干细胞移植治疗自身免疫性疾病的进展

间充质干细胞(MSC)是来源于发育早期中胚层的成体干细胞,具有高度增殖、自我更新能力、多向分化潜能、损伤组织修复功能和免疫抑制能力.该文综述间充质干细胞,主要是脐带间充质干细胞(hUMSCs)和骨髓间充质干细胞(BMMSC),用于移植治疗系统性红斑狼疮(SLE)、类风湿关节炎(RA)、硬皮病(SSc)、皮肌炎(DM)的研究进展,并显示间充质干细胞移植(MSCT)在未来的分子治疗中是非常有前景的一种方法.     

Treatment of chronic wounds with bone marrow-derived cells

BACKGROUND: Recent evidence indicates that bone marrow contains stem cells with the potential for differentiation into a variety of tissues, including endothelium, liver, muscle, bone, and skin. It may thus be plausible that bone marrow-derived cells can provide progenitor and/or stem cells to wounds during healing. Our objective in this study was to establish proof of principle that bone marrow-derived cells applied to chronic wounds can lead to closure of nonhealing wounds. We applied autologous bone marrow cells to chronic wounds in 3 patients with wounds of more than 1-year duration. These patients had not previously responded to standard and advanced therapies, including bioengineered skin application and grafting with autologous skin. OBSERVATIONS: Complete closure and evidence of dermal rebuilding was observed in all patients. Findings suggesting engraftment of applied cells was observed in biopsy specimens of treated wounds. Clinical and histologic evidence of reduced scarring was also observed. CONCLUSION: Directly applied bone marrow-derived cells can lead to dermal rebuilding and closure of nonhealing chronic wounds.     

Bone marrow cells differentiate into wound myofibroblasts and accelerate the healing of wounds with exposed bones when combined with an occlusive dressing

BACKGROUND: The usefulness of bone marrow cells in accelerating wound healing has not been evaluated despite increasing evidence that bone marrow contains mesenchymal stem cells that have multipotentiality to differentiate into various types of cells after they enter the microenvironment of a specific tissue (niche). OBJECTIVES: To determine the effects of bone marrow cells and occlusive dressings in promoting wound healing in rats. METHODS: We investigated by grafting, biopsy and immunohistochemistry whether various types of cells derived from green fluorescent protein (GFP)-transgenic rats would differentiate into wound component cells when administered topically on the wounds of rats. We also investigated whether topical application of bone marrow cells with an occlusive dressing would accelerate the healing of wounds with exposed bones, as measured by planimetry. RESULTS: GFP-labelled bone marrow cells contained multipotent stem cells that sufficiently differentiated into wound myofibroblasts presenting with alpha-smooth muscle actin in granulation tissue. Other types of cells, including myocytes, adipocytes, peripheral blood cells from buffy coat and dermal fibroblasts, did not express myofibroblast characteristics morphologically or immunohistochemically. Application of bone marrow cells and an occlusive dressing accelerated the repair of wounds with exposed bones, compared with an occlusive dressing only or with the topical administration of bone marrow cells plus a semidry to dry dressing. CONCLUSIONS: Our study indicates that bone marrow cells accelerate the healing of wounds at least in part through their differentiation into wound myofibroblasts. Thus, treatment of wounds with bone marrow cells and a supportive occlusive dressing is effective in promoting the formation of healthy granulation tissue and also for the preparation of an ideal wound bed.     

Stem cells in cutaneous wound healing

Treatment of chronic wounds remains difficult, in spite of better understanding of pathophysiologic principles and greater adherence to recognized standards of care. Even with recent advances stemming from breakthroughs in recombinant growth factors and bioengineered skin, up to almost 50% of chronic wounds that have been present for more than a year remain resistant to treatment. Because of these realities, there is excitement in the use of stem cells to offset impaired healing. Early data appear encouraging, but much work remains to be done. Although pilot studies suggest that multipotent adult stem cells can accelerate wound repair or even reconstitute the wound bed, the answers will need to come from randomized clinical trials. Thus far, considerable focus has been placed on bone marrow-derived mesenchymal stem cells, and there are now promising approaches for introducing them into the wound. It might turn out, however, that other types of stem cells will be more effective, including those derived from hair follicles or, perhaps, subsets of bone marrow-derived cultured cells. Still, proper wound care and adherence to basic principles cannot be bypassed, even by the most sophisticated approaches.     

Mesenchymal stem cell therapy in skin: why and what for?

In recent years, few stem cells have gained as much clinical notoriety as mesenchymal stem cells. Indeed, MSCs are already in use for a range of systemic inflammatory and autoimmune conditions that also affect the skin, such as acute and chronic graft versus host disease or lupus erythematosus. Most interestingly, these cells are able to improve skin wound healing in multiple preclinical models and few patient series. An additional potential of these cells is the delivery of missing structural elements in skin inherited disorders. However, we here contend that MSCs are not appropriate for cell replacement therapies in the context of wound healing. Indeed, engraftment of cells in the dermis is poor in the absence of irradiation and the observed effects seem mainly due to paracrine factors. In this viewpoint, we favour the hypothesis of a replete niche and competition with resident mesenchymal populations in the dermis not allowing the engraftment of newly delivered MSCs. Consequently, we propose that the benefit of MSCs may be at least in part reproduced by the growth factors or immunomodulatory molecules that they produce. In any case, the rapid progress in this field has allowed the emergence of important questions in skin biology that need to be addressed in parallel with the predictable future use of MSCs in the clinic.     

Neutral endopeptidase activity is increased in the skin of subjects with diabetic ulcers

Cutaneous sensory nerves mediate inflammation and wound healing by releasing neuropeptides, such as substance P, which stimulates pro-inflammatory responses by keratinocytes, fibroblasts, and endothelial cells. The cell surface enzyme, neutral endopeptidase, degrades substance P, thereby regulating its biologic actions. We hypothesized that neutral endopeptidase enzymatic activity is increased in chronic wounds and skin from subjects with diabetes. We compared cutaneous neutral endopeptidase expression and enzymatic activity between normal controls and diabetic subjects with neuropathy and chronic wounds. Skin samples from subjects with diabetes were taken at the time of amputation for nonhealing ulcers. Skin taken from the ulcer margin, 1 cm from the ulcer (adjacent), and from the most proximal region of the amputated leg were studied. Skin biopsies from the leg of healthy control subjects were also studied. Neutral endopeptidase was localized by immunohistochemistry in all tissue sections. Neutral endopeptidase activity was measured using a fluorimetric assay. The median neutral endopeptidase activity of the ulcer margin was 1.21 x higher (p>0.2) than adjacent skin, 5.26 (p<0.001) than proximal skin, and 15.22 x higher (p<0.001) than control skin. Adjacent skin had a median neutral endopeptidase activity 4.34 x higher (p<0.001) than proximal skin and 12.58 x higher (p<0.001) than control skin. The median neutral endopeptidase activity of proximal skin was 2.90 x higher (p<0.001) than control skin. This elevated neutral endopeptidase activity in the skin and chronic ulcers of subjects with diabetes combined with peripheral neuropathy may contribute to deficient neuroinflammatory signaling and may impair wound healing in subjects with diabetes.     

Mesenchymale Stammzellen der Haut

Within the next decade stem cell-based therapies can be expected to be part of clinical medicine. In regard to the skin, the focus of stem cell research is on the epidermis and the hair follicle. In 2001, mesenchymal stem cells residing within the dermis were first isolated which have the capacity to differentiate into adipocytes, smooth muscle cells, osteocytes, chondrocytes and even neurons and glia as well as hematopoietic cells of myeloid and erythroid lineage. The perifollicular connective tissue sheath and the papilla represent the likely anatomical niche for these multipotent dermal cells. They have the potential to function as an easily accessible, autologous source for future stem cell transplantation. Potential therapeutic applications include the treatment of acute and steroid-refractory graft-versus-host disease, systemic lupus erythematosus, idiopathic pulmonary fibrosis and arthritis. The neuronal differentiation potential of cutaneous mesenchymal stem cells may also be exploited in the treatment of neurodegenerative disorders and traumatic spinal injury. The most immediate impact can be expected in the field of wound healing.     

Macrophage‐derived GPNMB accelerates skin healing

Healing is a vital response important for the re‐establishment of the skin integrity following injury. Delayed or aberrant dermal wound healing leads to morbidity in patients. The development of therapies to improve dermal healing would be useful. Currently, the design of efficient treatments is stalled by the lack of detailed knowledge about the cellular and molecular mechanisms involved in wound healing. Recently, using state‐of‐the‐art technologies, it was revealed that macrophages signal via GPNMB to mesenchymal stem cells, accelerating skin healing. Strikingly, transplantation of macrophages expressing GPNMB improves skin healing in GPNMB‐mutant mice. Additionally, topical treatment with recombinant GPNMB restored mesenchymal stem cells recruitment and accelerated wound closure in the diabetic skin. From a drug development perspective, this GPNMB is a new candidate for skin healing.     

Tissue engineering for the management of chronic wounds: current concepts and future perspectives

Chronic wounds constitute a significant and growing biomedical burden. With the increasing growth of populations prone to dysfunctional wound healing, there is an urgent and unmet need for novel strategies to both prevent and treat these complications. Tissue engineering offers the potential to create functional skin, and the synergistic efforts of biomedical engineers, material scientists, and molecular and cell biologists have yielded promising therapies for non‐healing wounds. However, traditional paradigms for wound healing focus largely on the role of inflammatory cells and fail to incorporate more recent research highlighting the importance of stem cells and matrix dynamics in skin repair. Approaches to chronic wound healing centred on inflammation alone are inadequate to guide the development of regenerative medicine‐based technologies. As the molecular pathways and biologic defects underlying non‐healing wounds are further elucidated, multifaceted bioengineering systems must advance in parallel to exploit this knowledge. In this viewpoint essay, we highlight the current concepts in tissue engineering for chronic wounds and speculate on areas for future research in this increasingly interdisciplinary field.     

Multilineage differentiation potential of human dermal skin-derived fibroblasts

Dermal skin-derived fibroblasts from rodent and human have been found to exhibit mesenchymal surface antigen immunophenotype and differentiation potential along the three main mesenchymal-derived tissues: bone, cartilage and fat. Human dermal skin-derived mesenchymal stem cells constitute a promising cell source in clinical applications. Therefore, we isolated fibroblastic mesenchymal stem-cell-like cells from human dermis derived from juvenile foreskins, which share a mesenchymal stem cell phenotype and multi-lineage differentiation potential. We could show similar expression patterns for CD14(-), CD29(+), CD31(-), CD34(-), CD44(+), CD45(-), CD71(+), CD73/SH3-SH4(+), CD90/Thy-1(+), CD105/SH2(+), CD133(-) and CD166/ALCAM(+) in well-established adipose tissue derived-stem cells and fibroblastic mesenchymal stem-cell-like cells by flow cytometry. Immunostainings showed that fibroblastic mesenchymal stem-cell-like cells expressed vimentin, fibronectin and collagen; they were less positive for alpha-smooth muscle actin and nestin, while they were negative for epithelial cytokeratins. When cultured under appropriate inducible conditions, both cell types could differentiate along the adipogenic and osteogenic lineages. Additionally, fibroblastic mesenchymal stem-cell-like cells demonstrated a high proliferation potential. These findings are of particular importance, because skin or adipose tissues are easily accessible for autologous cell transplantations in regenerative medicine. In summary, these data indicate that dermal fibroblasts with multilineage differentiation potential are present in human dermis and they might play a key role in cutaneous wound healing.