Umbilical cord blood stem cells: Towards a proteomic approach

The first umbilical cord blood (UCB) transplant to a sibling with Fanconi's anaemia in 1988 represented a breakthrough in the field of transplantation. Thereon, several transplants have been performed with UCB-derived hematopoietic stem cells (HSCs) and a plethora of studies have investigated the plasticity of UCB-derived stem and progenitor cells. However, these studies have not been hitherto translated into clinical trials and, although UCB is routinely used as an alternative source of HSCs, no substantial advances have been made in the field of clinical regenerative medicine. The real deal is the lack of knowledge about the molecular processes governing the events of differentiation which transform immature UCB stem cells into terminally-committed hematopoietic, muscle, bone and nervous cells. In order to fill this void, several studies have been recently focused on the identification of the peculiar proteomic profile of UCB-derived stem cells.Hereby, we concisely review recent proteomic surveys addressing UCB-derived stem and progenitor cells.Notably, comparative studies detected a wider spectrum of proteins in immature cells rather than in more differentiated populations, as if maturation events could represent a bottleneck to protein expression. Future research projects should try to shed light on these processes and their completion could pave the way for unprecedented treatments.     

Hematopoietic stem cell expansion: challenges and opportunities

Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell population. Although hematopoietic stem cells (HSCs) will rapidly expand after in vivo transplantation, experience from in vitro studies indicates that control of HSPC self-renewal and differentiation in culture remains difficult. Protocols that are based on hematopoietic cytokines have failed to support reliable amplification of immature stem cells in culture, suggesting that additional factors are required. In recent years, several novel factors, including developmental factors and chemical compounds, have been reported to affect HSC self-renewal and improve ex vivo stem cell expansion protocols. Here, we highlight early expansion attempts and review recent development in the extrinsic control of HSPC fate in vitro.     

胚胎干细胞向血液干细胞定向分化的研究进展

骨髓移植是目前治疗恶性白血病以及遗传性血液病最有效的方法之一。但是HLA相匹配的骨髓捐献者严重短缺,骨髓造血干细胞（hematopoietic stem cells,HSCs）体外培养困难,在体外修复患者骨髓造血干细胞技术不成熟,这些都大大限制了骨髓移植在临床上的应用。多能性胚胎干细胞（embryonic stem cells,ESCs）具有自我更新能力,在合适的培养条件下分化形成各种血系细胞,是造血干细胞的另一来源。在过去的二十多年里,血发生的研究是干细胞生物学中最为活跃的领域之一。小鼠及人的胚胎干细胞方面的研究最近取得了重大进展。这篇综述总结了近年来从胚胎干细胞获得造血干细胞的成就,以及在安全和技术上的障碍。胚胎干细胞诱导生成可移植性血干细胞的研究能够使我们更好地了解正常和异常造血发生的机制,同时也为造血干细胞的临床应用提供理论和实验依据。     

Hematopoietic stem cell gene therapy for Niemann-Pick disease and other lysosomal storage diseases

Of the various gene therapy approaches under investigation for the treatment of genetic diseases, hematopoietic stem cell-mediated gene therapy has attracted the most interest. Enriched populations of hematopoietic stem cells can be obtained from diseased individuals, genetically modified to express normal gene products, and then transplanted back into these individuals without the risk of graft versus host disease. Following transplantation and engraftment, hematopoietically-derived cells can repopulate various sites of pathology and express the normal gene product in vivo. Such a procedure has been accomplished in several mouse models of human genetics diseases, leading to partial or complete correction of the disease phenotype, and current efforts are now focused on adapting the success of murine systems to larger animals, including man. This review will focus on the use of hematopoietic stem cell-mediated gene therapy for the treatment of lysosomal storage disorders, and discuss recent data obtained in the laboratory using a murine knock-out mouse model of Types A and B Niemann-Pick disease (NPD).     

The potential of stem cells for the treatment of brain tumors and globoid cell leukodystrophy

Stem cells of different origin are under careful scrutiny as potential new tools for the treatment of several neurological diseases. The major focus of these reaserches have been neurodegenerative disorders, such as Huntington Chorea or Parkinson Disease (Shihabuddin et al., 1999). More recently attention has been devoted to their use for brain repair after stroke (Savitz et al., 2002). In this review we will focus on the potential of stem cell treatments for glioblastoma multiforme (Holland, 2000), the most aggressive primary brain tumor, and globoid cell leukodystrophy (Krabbe disease), a metabolic disorder of the white matter (Berger et al., 2001). These two diseases may offer a paradigm of what the stem cell approach may offer in term of treatment, alone or in combination with other therapeutic approaches. Two kinds of stem cells will be consideredhere: neural stem cells and hematopoietic stem cells, both obtained after birth. The review will focus on experimental models, with an eye on clinical perspectives. This revised version was published online in July 2006 with corrections to the Cover Date.     

巨核细胞生成调控相关细胞因子及其作用研究进展

造血干细胞分化生成巨核细胞是一个十分复杂的过程,包括造血干细胞动员及其向巨核系祖细胞分化,巨核系祖细胞增殖、分化生成未成熟巨核细胞,巨核细胞的成熟和血小板释放等过程。研究发现,造血干细胞动员及其向各系细胞分化的大部分过程都在一种称为"龛"的结构中进行,多种龛内信号分子参与了造血干细胞的动员和分化调控。该文对造血干细胞龛内参与造血干细胞动员和分化生成巨核细胞的几种重要细胞因子及其调控作用进行综述。     

Recent trends in research on differentiation of hematopoietic cells and lymphokines (hemopoietins).

A recent trend in hematological research fields has been to isolate and characterize hematopoietic stem cells/progenitors and their growth factors (hemopoietins) to gain a much better understanding of the nature of the stem cell and the mechanisms regulating its development. It is generally accepted that all the various types of blood cells develop from a single progenitor called a hematopoietic stem cell. Quantitative studies of the function of hemopoietic stem cells began two decades ago with the development of a spleen colony assay, and then, clonal cell culture techniques for committed progenitors were developed with several models for hematopoietic differentiation being proposed. Within the last few years, some hormones have been discovered that are known as hematopoietic growth hormones or hemopoietins, each of which is of protein nature and causes specific classes of blood cells to be made and primed. These hormones also enhance the function of the mature cells, the genes of which have recently been cloned. On the other hand, long-term bone marrow culture has recently permitted detailed investigations of the relationship between hematopoietic cells and the microenvironment in which they are found, e.g. stromal cells, in vitro, relating to the regulation of cell proliferation and differentiation. Further, in hematological fields, other bioactive factors including differentiation-inducing compounds, e. g. bioactive glycosphingolipids, and leukocyte-endothelial cell recognition molecules (adhesion receptors) have been discovered, the molecular mechanism(s) of which have yet to be elucidated. This communication focuses on recent advances in research on soluble hemopoietins and other bioactive factors relating to differentiation-induction and to cell-to-cell recognition.     

Self-renewal and differentiation of hematopoietic stem cells: a molecular approach (a review)

Two characteristics define a hematopoietic stem cell: the ability to differentiate into all hematopoietic lineages, and the ability to maintain hematopoiesis over a life span by a self-renewal process. The mechanisms that regulate the fate of blood-forming cells in vivo, however, are poorly understood. Despite the ability to culture hematopoietic progenitor cells (committed to particular lineages), in vitro culture of self-renewing multipotent stem cells has not yet been achieved. What is clear that both intrinsic and extrinsic signals regulate hematopoietic stem cell fate and some of these signals have now been identified. which will be highlighted in this review.     

Leukemic stem cells show the way

The blood-related cancer leukemia was the first disease where human cancer stem cells (CSCs), or leukemic stem cells (LSCs), were isolated. The hematopoietic system is one of the best tissues for investigating cancer stem cells, since the developmental hierarchy of normal blood formation is well defined. Leukemia can now be viewed as aberrant hematopoietic processes initiated by rare leukemic stem cells (LSC) that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LSC and the mechanisms responsible for their emergence in the course of the disease. This report will review our current knowledge on leukemic stem cell development and finally demonstrate how these discoveries provide a paradigm for identification of Cancer Stem Cell (CSC) from solid tumors.     

Editing human hematopoietic stem cells: advances and challenges

Genome editing of hematopoietic stem and progenitor cells is being developed for the treatment of several inherited disorders of the hematopoietic system. The adaptation of CRISPR-Cas9-based technologies to make precise changes to the genome, and developments in altering the specificity and efficiency, and improving the delivery of nucleases to target cells have led to several breakthroughs. Many clinical trials are ongoing, and several pre-clinical models have been reported that would allow these genetic therapies to one day offer a potential cure to patients with diseases where limited options currently exist. However, there remain several challenges with respect to establishing safety, expanding accessibility and improving the manufacturing processes of these therapeutic products. This review focuses on some of the recent advances in the field of genome editing of hematopoietic stem and progenitor cells and illustrates the ongoing challenges.     

Skin-derived multipotent stromal cells – an archrival for mesenchymal stem cells

Progenitor stem cells have been identified, isolated and characterized in numerous tissues and organs. However, their therapeutic potential and the use of these stem cells remain elusive except for a few progenitor cells from bone marrow, umbilical cord blood, eyes and dental pulp. The use of bone marrow-derived hematopoietic stem cells (HSC) or mesenchymal stem cells (MSCs) is restricted due to their extreme invasive procedures, low differentiation potential with age and rejection. Thus, we need a clinical grade alternative to progenitor stem cells with a high potential to differentiate, na?ve and is relatively easy in in vitro propagation. In this review, we summarize cell populations of adherent and floating spheres derived from different origins of skin, or correctly foreskin, by enzymatic digestion compared with established MSCs. The morphology, phenotype, differentiation capability and immunosuppressive property of the adherent cell populations are comparable with MSCs. Serum-free cultured floating spheres have limited mesodermal but higher neurogenic differentation potential, analogous to neural crest stem cells. Both the populations confirmed their plethora potential in in vitro. Together, it may be noted that the skin-derived adherent cell populations and floating cells can be good alternative sources of progenitor cells especially in cosmetic, plastic and sports regenerative medicine.     

Molecular mechanisms underlying adhesion and migration of hematopoietic stem cells

Hematopoietic stem cell transplantation is the most powerful treatment modality for a large number of hematopoietic malignancies, including leukemia. Successful hematopoietic recovery after transplantation depends on homing of hematopoietic stem cells to the bone marrow and subsequent lodging of those cells in specific niches in the bone marrow. Migration of hematopoietic stem cells to the bone marrow is a highly regulated process that requires correct regulation of the expression and activity of various molecules including chemoattractants, selectins and integrins. This review will discuss recent studies that have extended our understanding of the molecular mechanisms underlying adhesion, migration and bone marrow homing of hematopoietic stem cells.     

Molecular mechanisms underlying adhesion and migration of hematopoietic stem cells

Hematopoietic stem cell transplantation is the most powerful treatment modality for a large number of hematopoietic malignancies, including leukemia. Successful hematopoietic recovery after transplantation depends on homing of hematopoietic stem cells to the bone marrow and subsequent lodging of those cells in specific niches in the bone marrow. Migration of hematopoietic stem cells to the bone marrow is a highly regulated process that requires correct regulation of the expression and activity of various molecules including chemoattractants, selectins and integrins. This review will discuss recent studies that have extended our understanding of the molecular mechanisms underlying adhesion, migration and bone marrow homing of hematopoietic stem cells.     

Circadian rhythm biochemistry: from protein degradation to sleep and mating

Hematopoiesis and the hepatic environment are known to have a close relationship at the time of hepatic development and systemic diseases. Recently, transplanted cells isolated from bone marrow of rodents and humans have been shown to differentiate into oval cells, which are considered to be hepatic stem cells, and hepatocytes in the liver. Then, purified hematopoietic stem cells were shown to have the ability to replace original liver cells in mice with hereditary tyrosinemia. In this review the interactions between hepatic stem cells are summarized and a hypothesis of hepatic differentiation will be proposed.     

Twisting immune responses for allogeneic stem cell therapy

Stem cell-derived tissues and organs have the potential to change modern clinical science. However, rejection of allogeneic grafts by the host's immune system is an issue which needs to be addressed before embryonic stem cell-derived cells or tissues can be used as medicines. Mismatches in human leukocyte class I antigens and minor histocompatibility antigens are the central factors that are responsible for various graft-versus-host diseases. Traditional strategies usually involve suppressing the whole immune systems with drugs. There are many side effects associated with these methods. Here, we discuss an emerging strategy for manipulating the central immune tolerance by naturally "introducing" donor antigens to a host so a recipient can acquire tolerance specifically to the donor cells or tissues. This strategy has two distinct stages. The first stage restores the thymic function of adult patients with sex steroid inhibitory drugs (LHRH-A), keratinocyte growth factor (KGF), interleukin 7 (IL-7) and FMS-like tyrosine kinase 3 (FLT3). The second stage introduces hematopoietic stem cells and their downstream progenitors to the restored thymus by direct injection. Hematopoietic stem cells are used to introduce donor antigens because they have priority access to the thymus. We also review several clinical cases to explain this new strategy.     

Preservation of stem cells

Adult stem cells (hematopoietic and mesenchymal) have demonstrated tremendous human therapeutic potential. Currently, human embryonic stem cells are used principally for understanding development and disease progression but also hold tremendous therapeutic potential. The ability to preserve stem cells is critical for their use in clinical and research applications. Preservation of cells permits the transportation of cells between sites, as well as completion of safety and quality control testing. Preservation also permits the development of a ‘manufacturing paradigm’ for cell therapies, thereby maximizing the number of products that can be produced at a given facility. In this article, we will review modes of preservation and the current status of preservation of hematopoietic, mesenchymal and human embryonic stem cells. Current and emerging issues in the area of stem cell preservation will also be described.     

Hematopoietic differentiation of embryonic stem cells

This review is focused on methods that are used to derive hematopoietic cells from embryonic stem cells (ESCs). One of the strategies that have been recently used to achieve this goal is an approach of mimicking the hematopoietic niche in vitro by using hematopoiesis-supportive feeder cells, cocktails of soluble hematopoietic growth factors and a variety of matrices. While there is clear evidence that it is possible to derive hematopoietic stem cells (HSCs) and subsequently committed hematopoietic progenitors and mature cells from ESCs, there remains the need to address multiple issues including the efficiency of HSCs derivation in vitro and their proper functionality.