Cellular therapies in organ transplantation

Cellular therapy is a promising tool for improving the outcome of organ transplantation. Various cell types with different immunoregulatory and regenerative properties may find application for specific transplant rejection or injury-related indications. The current era is crucial for the development of cellular therapies. Preclinical models have demonstrated the feasibility of efficacious cell therapy in transplantation, early clinical trials have shown safety of several of these therapies, and the first steps towards efficacy studies in humans have been made. In this review, we address the current state of the art of cellular therapies in clinical transplantation and discuss monitoring tools and endpoints for these studies.     

Stem cell transplantation as a therapeutic strategy for traumatic brain injury

Stem cell transplantation has enormous potential to be a viable therapeutic approach to replace the lost tissue/cells following traumatic brain injury (TBI). Several types of cell lines such as immortalized progenitors cells, embryonic rodent and human stem cells and bone marrow-derived cells have been successfully transplanted in experimental models of TBI, resulting in reduced neurobehavioral deficits and attenuation of histological damage. To date, it remains unclear whether stem cell are effective following transplantation into the injured brain via either cell replacement, trophic support, or manipulation of the local environment to stimulate endogenous neuroprotection/regeneration. This paper will review the most current and exciting pre-clinical data regarding the utility of cellular transplantation in experimental models of TBI. We believe that further work must continue to better understand the interaction between the host and the transplanted cells as well as the mechanisms regulating their differentiation into mature and functionally active neurons/glia.     

Caveats of mesenchymal stem cell therapy in solid organ transplantation

In the past decade, therapeutic use of mesenchymal stem cells (MSCs) has increased dramatically. The weight of existing evidence supports that the short‐term application of MSCs is safe and feasible; however, concerns remain over the possibility of unwanted long‐term effects. One fundamental difference between MSCs and pharmacotherapy is that, once applied, the effects of cell products cannot be easily reversed. Therefore, a carefully considered decision process is indispensable before cell infusion. In addition to unwanted interactions of MSCs with the host immune system, there are concerns that MSCs may promote tumor progression or even give rise to cancer themselves. As animal models and first‐in‐man clinical studies have provided conflicting results, it is challenging to estimate the long‐term risk of individual patients. In addition, most animal models, especially rodents, are ill‐suited to adequately address questions over long‐term side effects. Based on the available evidence, we address the potential pitfalls for the use of MSCs as a therapeutic agent to control alloimmune effects. The aim of this review was not to discourage investigators from clinical studies, but to raise awareness of the intrinsic risks of MSC therapy.     

A cell-based approach to the minimization of immunosuppression in renal transplantation.

Five renal transplant recipients were preoperatively treated with transplant acceptance-inducing cells (TAICs) in a Phase-I safety study of TAICs as an adjunct immune-conditioning therapy in living-donor kidney transplantation. Initially, patients received anti-thymocyte globulin induction therapy in combination with tacrolimus and steroid immunosuppression. Over the course of 12 weeks, steroids were withdrawn and tacrolimus therapy was minimized. Three of the five patients were able to tolerate low-dose tacrolimus monotherapy and one patient was withdrawn from all immunosuppression for over 8 months. No acute or delayed adverse events were associated with the infusion of TAICs. Monitoring of the recipient anti-donor reactivity of TAIC-treated patients in mixed lymphocyte cultures demonstrated that, during periods of clinically stable graft function, recipient T-cell proliferation and cytokine secretion in response to stimulation with donor alloantigen was relatively suppressed. Therefore, although the TAIC-II trial did not provide conclusive evidence of a beneficial effect of preoperative TAIC treatment, the results were encouraging because they suggest that TAICs promote a state of alloantigen-specific unresponsiveness, which might allow safe minimization of pharmacological immunosuppression.     

定向诱导间充质干细胞成软骨分化相关活性因子研究进展

关节软骨受损或缺失,是导致关节炎等渐进性疾病的主要原因,严重影响患者生活质量。成熟的透明软骨由于缺乏神经支配和血管供应,且软骨细胞增殖能力差,所以很难自我修复。自体软骨细胞移植尚存在局限性,且操作复杂,阻碍了临床应用。间充质干细胞增殖能力较强,并保留有分化潜力,但向成软骨分化需要一定的条件,如细胞因子、支架材料、培养基等。寻找促进诱导间充质干细胞成软骨分化的活性因子,是目前关节软骨再生的重要研究方向。本文就诱导间充质干细胞向软骨分化的相关活性因子的研究进展进行综述。     

Regenerative medicine as applied to solid organ transplantation: current status and future challenges

In the last two decades, regenerative medicine has shown the potential for “bench‐to‐bedside” translational research in specific clinical settings. Progress made in cell and stem cell biology, material sciences and tissue engineering enabled researchers to develop cutting‐edge technology which has lead to the creation of nonmodular tissue constructs such as skin, bladders, vessels and upper airways. In all cases, autologous cells were seeded on either artificial or natural supporting scaffolds. However, such constructs were implanted without the reconstruction of the vascular supply, and the nutrients and oxygen were supplied by diffusion from adjacent tissues. Engineering of modular organs (namely, organs organized in functioning units referred to as modules and requiring the reconstruction of the vascular supply) is more complex and challenging. Models of functioning hearts and livers have been engineered using “natural tissue” scaffolds and efforts are underway to produce kidneys, pancreata and small intestine. Creation of custom‐made bioengineered organs, where the cellular component is exquisitely autologous and have an internal vascular network, will theoretically overcome the two major hurdles in transplantation, namely the shortage of organs and the toxicity deriving from lifelong immunosuppression. This review describes recent advances in the engineering of several key tissues and organs.     

Regenerative medicine as a new therapeutic strategy for lower urinary tract dysfunction

The use of regenerative medicine for the treatment of organic and functional disorders intractable to conventional treatment has increased worldwide. This innovative medical field might particularly hold promise for the treatment of life‐threatening diseases or healing of irreplaceable organs, such as the heart, liver and brain. Dysfunction of the urogenital tract and associated organs other than the kidney might not have immediate life‐threatening implications; furthermore, the effectiveness of alternative therapy, such as enterocystoplasty for bladder cancer, has been shown. Therefore, most physicians or scientists do not give much importance to these disorders. However, urological disease has increased in developed societies in recent years. Furthermore, medical costs have also escalated. Disorders of the lower urinary tract, such as urinary disturbance or incontinence, can lead to other complications, impairing quality of life and ultimately increasing short‐ and long‐term medical expenses. Regenerative medicine might hold potential solutions to these problems. Recent advances in urogenital regenerative medicine are reviewed in the present article, with particular reference to lower urinary tract reconstruction. The potential of regenerative medicine for the treatment of intractable lower urinary tract dysfunction compared with conventional treatment is also discussed.     

HSCT联合不同剂量内皮祖细胞输注对小鼠造血重建的影响

目的 探讨异基因造血干细胞移植联合不同剂量内皮祖细胞(EPC)输注对移植后造血重建的影响.方法 以C57BL/6小鼠为供鼠,Balb/c小鼠为受鼠,进行HSCT,输注骨髓单个核细胞数量为5×106个/只.仅进行HSCT者为单纯骨髓细胞移植组;行HSCT的同时经尾静脉输注供者骨髓单个核细胞诱导培养的EPC的受鼠为EPC联合移植组,EPC的输注量分别为5×104、1×105、5× 105和1×106个/只.另设正常对照组和致死量照射组.观察小鼠的存活率、造血重建情况及骨髓微环境的变化.结果 各EPC联合移植组小鼠存活时间长于单纯骨髓移植组,5×105 EPC联合移植组至观察结束时存活率为100％,高于其他各组(P＜0.05).移植后10和15 d,5×105 EPC联合移植组外周血白细胞数量高于其他组(P＜0.05).移植后15 d,5×105 EPC联合移植组外周血血小板数量高于其他组(P＜0.05).5×105 EPC联合移植组造血组织增生程度也好于其他组.5×105 EPC联合移植组骨髓内HSC比例为(1.06±0.03)％,高于其他各组(P＜0.05).结论 小鼠异基因骨髓移植中联合输注5×105 EPC能够有效促进造血重建,提高小鼠存活率.     

Rituximab in recurrent idiopathic giant cell myocarditis after heart transplantation: a potential therapeutic approach

Giant cell myocarditis (GCM) is a very aggressive form of myocardial inflammation. While immunosuppressive therapy is usually able to keep under control the disease and prolong the average transplant‐free survival in many patients, effective therapeutic strategies to prevent or treat the recurrence of GCM in transplanted organs are still to be defined. We report the case of a young woman with idiopathic GCM who, despite immediate aggressive immunosuppressive therapy, rapidly progressed to irreversible heart failure and required urgent heart transplantation. Yet, 2 months later, the disease recurred in the transplanted heart, despite an intensive four‐drug antirejection regimen. The introduction of rituximab, an anti‐CD20 monoclonal antibody, 375 mg/m²/week i.v. for four consecutive weeks and then every 4 months as maintenance therapy, determined a complete and steady clinical remission of the disease. After nineteen months since rituximab administration, the patient is doing well and repeated follow‐up endo‐myocardial biopsies confirmed the complete resolution of myocardial inflammation. Our experience seems to suggest that rituximab can be a reasonably effective and safe therapeutic option in GCM recurring in transplanted organs.     

高剂量化疗合并自体造血干细胞移植治疗睾丸肿瘤

报告高剂量化疗＋自体造血干细胞移植（ＨＤＣ＋ＡＨＳＣＴ）治疗４例睾丸非精原细胞瘤（ＮＳＧＣＴ）的结果。预处理方案由环磷酰胺（３．０～３．５ｇ／Ｍ２）、足叶乙甙（７００～１０００ｍｇ／Ｍ２）、卡铂（６００～７５０ｍｇ／Ｍ２）组成。治疗中骨髓抑制均达Ⅳ度，无Ⅳ度髓外毒性出现。３例初治进展期患者治疗后１例完全缓解，２例部分缓解，其中１例在移植后６个月病情进展，另２例已持续缓解１５个月；１例复发患者治疗后肿瘤进展。认为ＨＤＣ＋ＡＨＳＣＴ治疗ＮＳＧＣＴ的适应证仍有待进一步探索，使用的预处理方案的剂量强度尚可进一步提高     

The current status of stem cell therapy in ischemic heart disease

The last decade has witnessed the publication of a number of stem cell clinical trials, primarily using bone marrow‐derived cells as the injected cell. Much has been learned through these “first‐generation” clinical trials. The advances in our understanding include (1) cell therapy is safe; (2) cell therapy has been mildly effective; and (3) human bone marrow‐derived stem cells do not transdifferentiate into cardiomyocytes or new blood vessels. The primary mechanism of action for cell therapy is now believed to be through paracrine effects that include the release of cytokines; chemokines; and growth factors that inhibit apoptosis and fibrosis, enhance contractility, and activate regenerative mechanisms through endogenous circulating or site‐specific stem cells. The current direction for clinical trials includes the use of stem cells capable of cardiac lineage.     

Stem cell transplantation and other novel techniques for promoting recovery from spinal cord injury

A number of potential approaches aim to optimize functional recovery after spinal cord injury. They include minimizing the progression of secondary injury, manipulating the neuroinhibitory environment of the spinal cord, replacing lost tissue with transplanted cells or peripheral nerve grafts, remyelinating denuded axons, and maximizing the intrinsic regenerative potential of endogenous progenitor cells. We review the application of stem cell transplantation to the spinal cord, emphasizing the use of embryonic stem cells for remyelinating damaged axons. We speculate that harnessing the potential of endogenously born stem cells already present in the spinal cord represents an important therapeutic target. We also discuss the potential application of peripheral nervous system reconstruction to recovery from spinal cord injury. The principles of peripheral nerve regeneration and concepts of nerve grafting are reviewed. Particular attention is given to peripheral nerve allotransplantation for repairing extensively injured tissue when autologous donor nerve material is scarce. The potential role of nerve transfers for reconstructing the injured spinal cord, particularly the cauda equina and lumbosacral plexus, are also described.     

Mesenchymal stem cell transplantation attenuates cardiac fibrosis associated with isoproterenol‐induced global heart failure

We aimed to examine the ability of transplanted mesenchymal stem cells (MSCs) to attenuate cardiac fibrosis caused by global heart failure, and investigate the mechanisms that are possibly mediating this effect. Global heart failure was induced in Wistar rats by isoproterenol injection. Four weeks later, MSCs were transplanted by intramyocardial injection, while control groups were treated by injection of cell culture medium alone. Four weeks after transplantation, heart function was assessed, and histologic and molecular analyses conducted. Compared with the medium‐treated group, MSC transplantation significantly decreased the expression of collagens I and III, and matrix metalloproteinase 2 and 9, but heart function was improved in MSC‐treated animals. In addition, expression of antifibrotic factor, hepatocyte growth factor (HGF), was detected in cultured MSCs, suggesting a possible mechanism underlying antifibrotic effects. Importantly, HGF expression levels were higher in MSC‐treated hearts, compared with medium‐treated hearts. Therefore, we could conclude that MSC transplantation can attenuate myocardial fibrosis in a rat model of global heart failure, and this may be at least partially mediated by paracrine signaling from MSCs via antifibrotic factors such as HGF.