Stem cells: tissue regeneration and cancer

Regenerative medicine is the promised paradigm of replacement and repair of damaged or senescent tissues. As the building blocks for organ development and tissue repair, stem cells have unique and wide-ranging capabilities, thus delineating their potential application to regenerative medicine. The recognition that consistent patterns of molecular mechanisms drive organ development and postnatal tissue regeneration has significant implications for a variety of pediatric diseases beyond replacement biology. The observation that organ-specific stem cells derive all of the differentiated cells within a given tissue has led to the acceptance of a stem cell hierarchy model for tissue development, maintenance, and repair. Extending the tissue stem cell hierarchical model to tissue carcinogenesis may revolutionize the manner in which we conceptualize cancer therapeutics. In this review, the clinical promise of these technologies and the emerging concept of "cancer stem cells" are examined. A basic understanding of stem cell biology is paramount to stay informed of this emerging technology and the accompanying research in this area with the potential for clinical application.     

Bone marrow transplantation: it's not just about blood anymore!

Abstract: Bone marrow transplantation is established as effective cell therapy for hematopoietic disorders. With the recognition that bone marrow also contains mesenchymal stem cells, with the potential to differentiate to a wide variety of mesenchymal tissues, bone marrow transplantation, in theory, may be used to treat many nonhematopoietic disorders as well. Here, we present an overview of the developments of clinically oriented marrow mesenchymal stem cell biology and it's early applications as adjunct cell therapy in conventional stem cell transplantation, and most importantly as stem cell therapy for nonhematopoietic disorders.     

Stem cell-based organ replacements—Airway and lung tissue engineering

Tissue engineering requires the use of cells seeded onto scaffolds, often in conjunction with bioactive molecules, to regenerate or replace tissues. Significant advances have been made in recent years within the fields of stem cell biology and biomaterials, leading to some exciting developments in airway tissue engineering, including the first use of stem cell-based tissue-engineered tracheal replacements in humans. In addition, recent advances within the fields of scaffold biology and decellularization offer the potential to transplant patients without the use of immunosuppression.     

Stem cell plasticity: a new image of the bone marrow stem cell

The central tenet of stem cell biology is that within tissues there reside stem cells with the capacity for both self-renewal and terminal differentiation to the multiple lineages of that tissue. Over the last few years, numerous studies have challenged this paradigm by showing that tissue stem cells can differentiate to unexpected cell lineages, suggesting an enormous plasticity of differentiation. The hematopoietic stem cell, which resides within bone marrow and gives rise to all blood cells, has been the focal point of these efforts. However, recent studies have disputed the notion of hematopoietic stem cell plasticity. In truth, stem cell plasticity, strictly defined, has yet to be rigorously proven. Both animal models to carefully address outstanding issues and pilot clinical trials to explore the therapeutic potential will be key elements to advance science for the benefit of patients.     

Routes to regenerating islet cells: stem cells and other biological therapies for type 1 diabetes

Abstract:  New biological therapies for type 1 diabetes are emerging from the forefront of stem cell and islet cell biology. Basic research in animal models has uncovered a variety of mechanisms by which natural regeneration of pancreatic islet cells occurs, despite the underlying autoimmune defect. Two mechanisms – in particular, β-islet cell proliferation and stem cell differentiation – can be harnessed in innovative ways in order to regenerate islets lost to disease. This review provides a background on stem cells and describes a range of potential biological therapies for type 1 diabetes, including the use of adult stem cells from the spleen, an organ not previously considered a source of pancreatic stem cells. Stem cells of the spleen have been demonstrated to home to the pancreas, where they mature into fully functional islet cells responsible for restoring normoglycemia. If the underlying autoimmune defect can be eradicated, stem cells of the spleen, as well as related strategies, can be used in order to regrow islets destroyed by type 1 diabetes.     

Extracellular control of pancreatic differentiation

Our understanding of basic mechanisms of differentiation has evolved rapidly in the last two decades. Spurred by advances in molecular biology and other research technologies, these advances have become of heightened importance with the recent advent of the possibility of engineering different types of stem cells into needed cell and tissue sources. As pediatric surgeons, we have the potential to play a key role in interfacing between the basic science necessary to understand differentiation processes, and its application at the bedside. In this brief article, we outline our in-depth analysis of mechanisms of basic differentiation of pancreatic precursor cells in an effort to better understand ways in which we can engineer a stem cell pool to form mature pancreatic cells.     

Cellular therapies based on stem cells and their insulin‐producing surrogates: a 2015 reality check

Stem cell technology has recently gained a substantial amount of interest as one method to create a potentially limitless supply of transplantable insulin‐producing cells to treat, and possibly cure diabetes mellitus. In this review, we summarize the state‐of‐the art of stem cell technology and list the potential sources of stem cells that have been shown to be useful as insulin‐expressing surrogates. We also discuss the milestones that have been reached and those that remain to be addressed to generate bona fide beta cell‐similar, insulin‐producing surrogates. The caveats, limitations, and realistic expectations are also considered for current and future technology. In spite of the tremendous technical advances realized in the past decade, especially in the field of reprogramming adult somatic cells to become stem cells, the state‐of‐the art still relies on lengthy and cumbersome in vitro culture methods that yield cell populations that are not particularly glucose‐responsive when transplanted into diabetic hosts. Despite the current impediments toward clinical translation, including the potential for immune rejection, the availability of technology to generate patient‐specific reprogrammable stem cells has, and will be critical for, important insights into the genetics, epigenetics, biology, and physiology of insulin‐producing cells in normal and pathologic states. This knowledge could accelerate the time to reach the desired breakthrough for safe and efficacious beta cell surrogates.     

BIOLOGY AND CLINICAL UTILITY OF HEMATOPOIETIC STEM CELLS

Stem cell transplantation (SCT) was developed to treat patients with malignancies and fatal disorders of hematopoiesis. For patients with malignancies, SCT allows the use of higher doses of chemotherapy +/- radiation than recipients of conventional therapy. For patients with defects in hematopoietic cells, chemotherapy is necessary to prevent rejection of the donor stem cells. The infusion of normal hematopoietic stem cells following high-dose therapy minimizes the duration of pancytopenia and replaces defective stem cells with those from a normal donor. The first successful transplants used stem cells from HLA-matched donors. At that time, the use of stem cells from partially matched allogeneic donors was limited by the difficulty in preventing, diagnosing, and treating graft-versus-host disease (GvHD). The early success seen with leukemia and nonmalignant diseases led to the expansion of the indications for SCT and has transformed SCT from an experimental procedure performed by limited number of centers to an accepted part of the treatment of cancer. Today, successful SCTs are performed using autologous stem cells, stem cells from HLA matched, related donors; partially matched, related donors; unrelated donors, and from related and unrelated umbilical cord blood. The successes seen with these stem cell sources are the result of several advances in transplantation biology. We now have a better understanding of the relationship between residual host immunity and rejection and have used this information to develop more immunosuppressive preparative therapies capable of preventing rejection. We have a better understanding of the relationship between T cells and GvHD and have developed more effective methods to prevent and treat severe GvHD . We also have a better understanding of stem cell physiology that has resulted in our ability to quantitate hematopoietic progenitors and identify the cytokines important in inducing stem cell proliferation in vitro and in vivo. This paper reviews the recent advances in stem cell biology and how those advances impact on clinical stem cell transplantation.     

Transformation of childhood MDS-refractory anemia to acute lymphoblastic leukemia

Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cell. Patients have a deteriorating course with about 30% evolving into acute leukemias usually of the myeloid phenotype. Evolution into acute lymphoblastic leukemia is a rare and intriguing phenomenon seen in far less than 1% of adult cases, and extremely rare in pediatric population. We report a case of childhood MDS-refractory anemia transforming into acute lymphoblastic leukemia after an interval of 21 months since presentation and being on cyclosporine therapy for 9.5 months. The case raises further questions about the biology of MDS and the potential role of cyclosporine in leukemic transformation.     

儿童急性髓系白血病分子生物学相关研究进展

儿童急性髓系细胞白血病是一种造血干细胞恶性克隆性疾病,其中分子生物学异常在急性髓系白血病发生发展中起了关键作用.随着技术的进步,越来越多的分子异常被发现,这为患者的预后评估及靶向治疗提供依据.     

The role of stem cells in fibrous dysplasia of bone and the Mccune-Albright syndrome

Stem cells have become a major area of interest in the treatment of human disease, but more recently, stem cells have come to be appreciated as the cause of disease. Fibrous dysplasia of bone and the McCune-Albright Syndrome evolve from activating missense mutations in Gsalpha in pluripotent embryonic stem cells. The legacy of these mutations remains in a population of mutated multipotent post-natal skeletal stem cells ("mesenchymal" stem cells), which direct the formation of abnormal bone and a fibrotic marrow in fibrous dysplasia. Future therapeutic approaches for the treatment of fibrous dysplasia, the most significant component of the McCune-Albright Syndrome, will depend on a greater understanding of post-natal skeletal stem cell biology and how skeletal stem cells can be manipulated for efficient bone regeneration.     

Stem cells in pediatric cardiology

The ability to reprogram virtually any cell of human origin to behave like embryonic or pluripotent stem cells is a major breakthrough in stem cell biology. Human induced pluripotent stem cells (iPSC) provide a unique opportunity to study “disease in a dish” within a defined genetic and environmental background. Patient-derived iPSCs have been successfully used to model cardiomyopathies, rhythm disorders and vascular disorders. They also provide an exciting opportunity for drug discovery and drug repurposing for disorders with a known molecular basis including childhood onset heart disease, particularly cardiac genetic disorders. The review will discuss their use in drug discovery, efficacy and toxicity studies with emphasis on challenges in pediatric-focused drug discovery. Issues that will need to be addressed in the coming years include development of maturation protocols for iPSC-derived cardiac lineages, use of iPSCs to study not just cardiac but extra-cardiac phenotypes in the same patient, scaling up of stem cell platforms for high-throughput drug screens, translating drug testing results to clinical applications in the paradigm of personalized medicine, and improving both the efficiency and the safety of iPSC-derived lineages for future stem cell therapies.     

Stem cells bioprocessing: an important milestone to move regenerative medicine research into the clinical arena

Regenerative Medicine is a new, multidisciplinary field that combines expertise in biology, chemistry, engineering, materials, and medicine, to find solutions to some of the most challenging medical problems faced by humankind. Regenerative Medicine has the potential to impact the whole spectrum of health care, such as heart disease, emphysema, and diabetes. Regenerative Medicine employs various combinations of specially grown cells, tissues, and laboratory-made compounds to replace or amplify the body's natural healing process. The impact of Regenerative Medicine to the health care industry is likely to be comparable with that of antibiotics, vaccines and lately, monoclonal antibodies have had in clinical care. Regenerative Medicine is growing and maturing steadily; however, many challenges lie ahead. These include best cell source, most appropriate biomaterials, and reliable ways of expanding the cells and growing them in a three-dimensional environment (stem cell bioprocessing). This concise review deals with current achievements in the field, challenges that lie ahead and potential ways of having robust and reliable "off the shelf" cellular products.     

Proliferation and differentiation characteristics of neural stem cells during course of cerebral cortical histogenesis

Recent advancements in the research field of stem cell biology have enabled the realization of regenerative medicine in various systems of the body, including the central nervous system. However, fundamental knowledge regarding how neural stem cells divide and generate young neurons in mammals, especially in vivo, is still inadequate. In this article, we shall summarize the concept of cell cycle/division of neural stem cells that generate projection neurons in the murine cerebral cortex. We shall also review the molecular mechanisms that modulate the critical parameters related to the cell cycle regulatory mechanisms, with special reference to the cell cycle regulatory protein p27^Kip1, an inhibitor of progression of the cell cycle at the G1 phase. A better understanding of the mechanisms controlling cell cycle progression is expected to contribute to the development of novel strategies to increase the efficiency of neural cell/tissue production, both in vivo and in vitro.     

Stem cells: research tools and clinical treatments

The term 'stem cell' most commonly refers to embryonic stem cells, particularly in the lay media; however, it also describes other cell types. A stem cell represents a cell of multi-lineage potential with the ability for self-renewal. It is now clear that the plasticity and immortality of a given stem cell will depend on what type of stem cell it is, whether an embryonic stem cell, a fetal-placental stem cell or an adult stem cell. Stem cells offer great promise as cell-based therapies for the future. With evolving technology, much of the socio-political debate regarding stem cells can now be avoided.     

Autoimmune hemolytic anemia and immune thrombocytopenia following hematopoietic stem cell transplant: A critical review of the literature

Autoimmune cytopenias (AIC) post‐hematopoietic stem cell transplant (HSCT) are rare but exceptionally challenging complication. We conducted a comprehensive literature review and identified a pooled incidence of post‐HSCT autoimmune hemolytic anemia and/or immune thrombocytopenia of 2.66% (SE = 0.27) in pediatric patients. Nonmalignant disease, unrelated donor transplant, peripheral or cord blood stem cell source, conditioning regimen without total body irradiation, and presence of chronic graft‐versus‐host disease were prominent risk factors. Treatment was highly variable, and cytopenias were commonly refractory. AIC represent a significant post‐HSCT complication. We report here the incidence, risk factors, and possible biology behind the development of AIC in pediatric post‐HSCT patients.     

Stem cells and biopharmaceuticals: Vital roles in the growth of tissue-engineered small intestine

Tissue engineering currently constitutes a complex, multidisciplinary field exploring ideal sources of cells in combination with scaffolds or delivery systems in order to form a new, functional organ to replace native organ lack or loss. Short bowel syndrome (SBS) is a life-threatening condition with high morbidity and mortality rates in children. Current therapeutic strategies consist of costly and risky allotransplants that demand lifelong immunosuppression. A promising alternative is the implantation of autologous organoid units (OU) to create a tissue-engineered small intestine (TESI). This strategy is proven to be stem cell and mesenchyme dependent. Intestinal stem cells (ISCs) are located at the base of the crypt and are responsible for repopulating the cycling mucosa up to the villus tip. The stem cell niche governs the biology of ISCs and, together with the rest of the epithelium, communicates with the underlying mesenchyme to sustain intestinal homeostasis. Biopharmaceuticals are broadly used in the clinic to activate or enhance known signaling pathways and may greatly contribute to the development of a full-thickness intestine by increasing mucosal surface area, improving blood supply, and determining stem cell fate. This review will focus on tissue engineering as a means of building the new small intestine, highlighting the importance of stem cells and recombinant peptide growth factors as biopharmaceuticals.     

干细胞移植在肾脏疾病中的应用

该文总结干细胞移植在肾脏损伤修复中的治疗证据,着重讨论干细胞种类的选择、移植方法的选择、干细胞抵达肾脏的可能机制和它起效的可能机制。脐带间充质干细胞的应用具有广阔的前景,但细胞移植的途径和最佳剂量仍有待进一步研究。干细胞抵达肾脏的机制可能和靶部位表达和释放趋化干细胞的因子有关,而干细胞的旁分泌和内分泌功能可能是它发挥作用的主要的机制。关于干细胞移植治疗肾脏疾病还有许多问题有待解决,但是干细胞移植仍是急慢性肾脏疾病的治疗中一个充满前景和希望的治疗策略。     

Stem cell medicine: umbilical cord blood and its stem cell potential

The ultimate aim of stem cell research is to improve patient outcomes and quality of life, and/or to effect a cure for a variety of inherited or acquired diseases. Improved treatments rely on developments in stem cell therapies and the discovery of new therapeutic drugs that regulate stem cell functions. These complement each other for the repair, regeneration and replacement of damaged or defective tissues. Stem cells may be sourced or derived from blood and tissues postnatally ('adult' stem cells), from the fetus (fetal stem cells) or from the blastocyst in the developing embryo prior to implantation (embryonic stem cells), each forming a unique component of the revolution in stem cell research and therapies. This review will concentrate on recent developments in the use of haemopoietic stem cells from umbilical cord blood for the transplantation of patients with haematological disorders. It will conclude with a summary of the potential of other umbilical cord blood-derived stem cells for tissue repair or regeneration.     

干细胞向神经细胞诱导分化的研究进展

干细胞的无限自我更新和增殖分化的特性,为治疗神经系统疾病带来了希望,其中间充质干细胞(MSCs)具有分化成间质起源的任意组织包括神经组织的潜能,使其作为最佳种子细胞在组织工程中令人看好.但不少学者对间充质干细胞的这种可塑性持相反意见.神经干细胞可分化为不同类型的神经细胞,大多神经干细胞移植实验显示胶质细胞占较大比例.胚胎干细胞可分化为包括神经谱系在内的各种细胞谱系,目前有3种分化为神经细胞的方法,包括视黄酸诱导法、谱系选择法及基质细胞诱导法.少突胶质前体细胞是一种重要的神经前体细胞,表达趋化因子受体CXCR4,并受到CXCLl2的调节.血小板衍生生长因子、纤毛状神经营养因子与白血病抑制因子都可促进其分化.