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Full name for stem cells

Full name for stem cells


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So during research, my professor mentioned a type of stem cell, a name that was like 5-6 words long, that can be used to treat diabetes by creating an "artificial organ". That hypothetical organ would then be used to create insulin or treat diabetes using other methods.

However I can not remember that name for my life…

This community may not be able to assist me much, as I am aware of the many types of stem cells. This is all the information I have access to, and I cannot contact my professor until the weekend, so it would be great if I could get some prior knowledge about these stem cells; I just need to know the name…

Thanks in advance.


Human Embyronic Stem Cells (hESC) can be programmed to differentiate into a number of different types of tissue depending on the signals you give or withhold.

Source: BioTime

The company Viacyte is actually developing a technology based on hESC that can be used to rescue loss of function in type-1 diabetes, just as an example. Their process takes hESC to pancreatic endoderm after about a month. The pancreatic endoderm has the capacity to differentiate into beta cells, ductal cells and so forth. He could have also been talking about human induced pluripotent stem cells (hiPSC). Like embryonic stem cells, these can differentiate into "anything," but are derived differently.


Mesenchymal Stem Cells: Time to Change the Name!

Mesenchymal stem cells (MSCs) were officially named more than 25 years ago to represent a class of cells from human and mammalian bone marrow and periosteum that could be isolated and expanded in culture while maintaining their in vitro capacity to be induced to form a variety of mesodermal phenotypes and tissues. The in vitro capacity to form bone, cartilage, fat, etc., became an assay for identifying this class of multipotent cells and around which several companies were formed in the 1990s to medically exploit the regenerative capabilities of MSCs. Today, there are hundreds of clinics and hundreds of clinical trials using human MSCs with very few, if any, focusing on the in vitro multipotential capacities of these cells. Unfortunately, the fact that MSCs are called "stem cells" is being used to infer that patients will receive direct medical benefit, because they imagine that these cells will differentiate into regenerating tissue-producing cells. Such a stem cell treatment will presumably cure the patient of their medically relevant difficulties ranging from osteoarthritic (bone-on-bone) knees to various neurological maladies including dementia. I now urge that we change the name of MSCs to Medicinal Signaling Cells to more accurately reflect the fact that these cells home in on sites of injury or disease and secrete bioactive factors that are immunomodulatory and trophic (regenerative) meaning that these cells make therapeutic drugs in situ that are medicinal. It is, indeed, the patient's own site-specific and tissue-specific resident stem cells that construct the new tissue as stimulated by the bioactive factors secreted by the exogenously supplied MSCs. Stem Cells Translational Medicine 20176:1445-1451.

Keywords: MSCs Medicinal signaling cells Mesenchymal stem cells Regenerative medicine.

© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Figures

The mesengenic process. This hypothesis…

The mesengenic process. This hypothesis was originally verbalized in crude form in 1988…


What are Embryonic Stem Cells Used For?

In medicine and research, scientists use pluripotent embryonic stem cells. These cells do not have the ability to become an entire organism. Rather, they are directed by signals from the early embryo which tell them which cell type to differentiate into. Scientists prefer these cells for many reasons.

The use of embryonic stem cells is a very new form of medicine. For decades, the cause of many degenerative diseases and physical injuries has been understood. Tissue damage is the root cause of many of these ailments, and scientists have long been searching for a method of growing tissues which do not easily repair themselves. Because an embryonic stem cell is pluripotent and can become almost any cell in the body, these cells have long been studied for their possible use in medicine.

Since the late 1950’s scientists have been trying to test various methods of growing tissue with an embryonic stem cell. The first clinical trials were in the late 1960s, but not much progress has been made. President Bush put a moratorium on using Federal funds for stem cell research, which was finally lifted by the Obama Administration in 2009. European countries have also faced an uphill battle in funding stem cell research. However, with advances in the science came new discoveries which allowed for more ethical harvesting of an embryonic stem cell. The first treatments with medicinal stem cells were in 2010.

Regenerating Nerve Cells

Medically, the embryonic stem cell is limited in its current uses, though many novel applications are in the works. Current treatments focus on the replacement of damaged tissue from injury or disease. Of these, the first treatment approved by the FDA to undergo trials was replacing damaged tissue in spinal injuries.

Because nerve cells rarely regenerate, an embryonic stem cell can be used to replace the damaged nerve and restore function. In someone with a spinal injury, this means being able to walk again. For a blind person, this might mean being able to see again. While the treatment is still new and success is limited, it has shown some positive results.

As a Research Tool

Still, other medical advances are made with the embryonic stem cell, although these don’t come as direct medical treatments but rather as the knowledge that stem cells give us. As an embryonic stem cell differentiates into its target tissue, scientists can study the chemicals and methods it uses to do so. Scientists can also alter the genome of these cells, and study the effects different mutations have on a cell’s functioning.

Between these two paths of discovery, scientists have assembled much information about how and why cells differentiate and divide. Using these tools, scientists are closing in on methods which would allow them to turn regular cell back into a pluripotent stem cell. These are known as induced pluripotent stem cells. They are not embryonic stem cells, because they are not derived from an embryo. This process could not only fix injuries and ailments but could potentially reverse aging and prevent death.

On a less dramatic and grand scale, these methods are also being used to cure common diseases, such as diabetes. By learning how embryonic stem cells become pancreas cells and secrete insulin, scientists are learning the methods of converting other tissues to insulin-secreting tissues. This could help cure diabetes, often caused by the destruction of insulin-producing cells. If these were replaced with stem cells, or other cells were induced to become pancreas cells, the disease could be cured.

Other diseases, like cystic fibrosis, fragile x syndrome, and other genetic disorders are studied in embryonic stem cells. Not only can many cells be created, but they can be differentiated into different cell types. In this way, a scientist can build a picture of the disease from snapshots of each cell type, and understand exactly how the disease is affecting a person.


Full name for stem cells - Biology

Regenerative Medicine encompasses many fields of science and medicine.  The image below effectively portrays the scope of Regenerative Medicine as the umbrella, it covers many fields of research and clinical practice. Stem cell research and therapies continue to enhance the field of Regenerative Medicine and what it offers patients and scientists.  Stem cells have and will continue to play a critical role in scientific discoveries through developmental biology and therapeutic applications, however, we should be mindful to not limit our descriptions or thoughts regarding Regenerative Medicine and it’s capabilities to stem cell research alone.  The only constraints placed around it are the ones we set, as those in the field seek to uncover the intricacies of our biological systems.

Typically, when the term ‘Regenerative Medicine’ arises people automatically think about stem cells, particularly, embryonic stem cells.  Being that embryonic stem cell research is currently a highly debated topic in both the scientific and political field, the assumption that Regenerative Medicine Research only involves embryonic stem cell research can be narrowing to the field and does not allow one to understand its full potential.  While all stem cell work is vital to the advancement of Regenerative Medicine research and therapies, we cannot interchange the two terms as equals.  As we learn more about Regenerative Medicine, we must broaden our minds, so as not to limit the vast possibilities that Regenerative Medicine researchers seek to find in the inherent mysteries of our biological systems.  

How are stem cells and Regenerative Medicine linked? 

As discussed in other portions of this site, Regenerative Medicine is a comprehensive term used to describe the current methods and research employed to revive and/or replace dead or damaged tissue.  A portion of Regenerative Medicine research revolves around the use of stem cells, including embryonic, adult, and induced pluripotent stem cells (iPS), however there are many other resources that are utilized in order to carry out the mission of Regenerative Medicine research. These include transplants, biomaterials, scaffolds, machines and electronics, stimulation pathways, drug therapy, and many others.  This is thoroughly discussed on the ‘What is Regenerative Medicine?’ page. 

Stem cells have a very important role in Regenerative Medicine Research and have many potential applications.  First, because of their role in development and their potential to develop into many different cells types, stem cells are vital to the field of developmental biology.  Developmental biologists seek to uncover what genes and pathways are involved in cell differentiation (how cells develop into specific cell types such as liver, skin, or muscle cells) and how these can be manipulated to create new healthy tissues.  Second, stem cells can be applied to drug testing and development.  New drugs that are developed in Pharma could be safely and effectively tested using differentiated stem cells.  As scientists learn more about how stem cells develop to form new tissue they will be able to apply their knowledge in maintaining differentiated cell types that can be used to test particular drugs.  This method is already underway in the cancer therapy world, where cancer cells and grown in the laboratory for the purpose of testing anti-tumor and chemotherapeutic drugs.  Finally, and of most interest to patients and scientists is the role stem cells will play in Cell-Based Therapy.  These therapies will apply the understanding of stem cell development, differentiation, and maintenance to generate new, healthy tissue for diseases needing transplant or replacement of damaged tissue, such as arthritis, Parkinson's disease, type 1 diabetes, and coronary disease.  Cell therapies may one day be able to replace organ donation and eliminate the issues that accompany it such as rejection and tissue insufficiency.   Although there are still many difficulties surrounding the field of stem cell research and therapy, over the coming decades scientists hope to continue to make discoveries that will enable the potentials of cell-based therapy to become a reality. 


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Sources of Stem Cells

Pluripotent

Pluripotent stem cells being used in research today mainly come from embryos, hence the name, 𠇎mbryonic stem cells”. Pre-implantation embryos a few days old contain only 10-15% pluripotent cells in the “inner cell mass” ( Figure 1 ). Those pluripotent cells can be isolated, then cultured on a layer of �r” cells which provide unknown cues for many rounds of proliferation while sustaining their pluripotency.

Recently, two different groups of scientists induced adult cells back into the pluripotent state by molecular manipulation to yield “induced pluripotent stem cells” (iPS) that share some of the same characteristics as embryonic stem cells such as proliferation, morphology and gene expression (in the form of distinct surface markers and proteins being expressed). 4-8 Both groups used retroviruses to carry genes for transcription factors into the adult cells. These genes are transcribed and translated into proteins that regulate the expression of other genes designed to reprogram the adult nucleus back into its embryonic state. Both introduced the embryonic transcription factors known as Sox2 and Oct4. One group also added Klf4 and c-Myc 4 , and the other group added Lin28 and Nanog. 6 Other combinations of factors would probably also work, but, unfortunately, neither the retroviral carrier method nor the use of the oncogenic transcription factor c-Myc are likely to be approved for human therapy. Consequently, a purely chemical approach to deliver genes into the cells, and safer transcription factors are being tried. Results of these experiments look promising. 9

Multipotent

Multipotent stem cells may be a viable option for clinical use. These cells have the plasticity to become all the progenitor cells for a particular germ layer or can be restricted to become only one or two specialized cell types of a particular tissue. The multipotent stem cells with the highest differentiating potential are found in the developing embryo during gastrulation (day 14-15 in humans, day 6.5-7 in mice). These cells give rise to all cells of their particular germ layer, thus, they still have flexibility in their differentiation capacity. They are not pluripotent stem cells because they have lost the ability to become cells of all three germ layers ( Figure 1 ). On the low end of the plasticity spectrum are the unipotent cells that can become only one specialized cell type such as skin stem cells or muscle stem cells. These stem cells are typically found within their organ and although their differentiation capacity is restricted, these limited progenitor cells play a vital role in maintaining tissue integrity by replenishing aging or injured cells. There are many other sub-types of multipotent stem cells occupying a range of differentiation capacities. For example, multipotent cells derived from the mesoderm of the gastrula undergo a differentiation step limiting them to muscle and connective tissue however, further differentiation results in increased specialization towards only connective tissue and so on until the cells can give rise to only cartilage or only bone.

Multipotent stem cells found in bone marrow are best known, because these have been used therapeutically since the 1960’s 10 (their potential will be discussed in greater detail in a later section). Recent research has found new sources for multipotent stem cells of greater plasticity such as the placenta and umbilical cord blood. 11 Further, the heart, until recently considered void of stem cells, is now known to contain stem cells with the potential to become cardiac myocytes. 12 Similarly, neuro-progenitor cells have been found within the brain. 13

The cardiac stem cells are present in such small numbers, that they are difficult to study and their function has not been fully determined. The second review in this series will discuss their potential in greater detail.


Definition Edit

While the terms mesenchymal stem cell (MSC) and marrow stromal cell have been used interchangeably for many years, neither term is sufficiently descriptive:

    is embryonicconnective tissue that is derived from the mesoderm and that differentiates into hematopoietic and connective tissue, whereas MSCs do not differentiate into hematopoietic cells. [5] are connective tissue cells that form the supportive structure in which the functional cells of the tissue reside. While this is an accurate description for one function of MSCs, the term fails to convey the relatively recently discovered roles of MSCs in the repair of tissue. [6]
  • The term encompasses multipotent cells derived from other non-marrow tissues, such as placenta, [7]umbilical cord blood, adipose tissue, adult muscle, corneal stroma[8] or the dental pulp of deciduous (baby) teeth. [9] The cells do not have the capacity to reconstitute an entire organ.

Morphology Edit

Mesenchymal stem cells are characterized morphologically by a small cell body with a few cell processes that are long and thin. The cell body contains a large, round nucleus with a prominent nucleolus, which is surrounded by finely dispersed chromatin particles, giving the nucleus a clear appearance. The remainder of the cell body contains a small amount of Golgi apparatus, rough endoplasmic reticulum, mitochondria and polyribosomes. The cells, which are long and thin, are widely dispersed and the adjacent extracellular matrix is populated by a few reticular fibrils but is devoid of the other types of collagen fibrils. [10] [11] These distinctive morphological features of mesenchymal stem cells can be visualized label-free using live cell imaging.

Bone marrow Edit

Bone marrow was the original source of MSCs, [12] and still is the most frequently utilized. These bone marrow stem cells do not contribute to the formation of blood cells and so do not express the hematopoietic stem cell marker CD34. They are sometimes referred to as bone marrow stromal stem cells. [13]

Cord cells Edit

The youngest and most primitive MSCs may be obtained from umbilical cord tissue, namely Wharton's jelly and the umbilical cord blood. However MSCs are found in much higher concentration in the Wharton's jelly compared to cord blood, which is a rich source of hematopoietic stem cells. The umbilical cord is available after a birth. It is normally discarded and poses no risk for collection. These MSCs may prove to be a useful source of MSCs for clinical applications due to their primitive properties and fast growth rate. [14]

and these have several advantages over bone marrow-derived MSCs. Adipose tissue-derived MSCs (AdMSCs), in addition to being easier and safer to isolate than bone marrow-derived MSCs, can be obtained in larger quantities. [12] [15]

Molar cells Edit

The developing tooth bud of the mandibular third molar is a rich source of MSCs. While they are described as multipotent, it is possible that they are pluripotent. They eventually form enamel, dentin, blood vessels, dental pulp and nervous tissues. These stem cells are capable of differentiating into chondrocytes, cardiomyocytes, melanocytes, and hepatocyte‐like cells in vitro. [9]

Amniotic fluid Edit

Stem cells are present in amniotic fluid. As many as 1 in 100 cells collected during amniocentesis are pluripotent mesenchymal stem cells. [16]

Differentiation capacity Edit

MSCs have a great capacity for self-renewal while maintaining their multipotency. Recent work suggests that β-catenin, via regulation of EZH2, is a central molecule in maintaining the "stemness" of MSC's. [17] The standard test to confirm multipotency is differentiation of the cells into osteoblasts, adipocytes and chondrocytes as well as myocytes.

MSCs have been seen to even differentiate into neuron-like cells, [18] but doubt remains about whether the MSC-derived neurons are functional. [19] The degree to which the culture will differentiate varies among individuals and how differentiation is induced, e.g., chemical vs. mechanical [20] and it is not clear whether this variation is due to a different amount of "true" progenitor cells in the culture or variable differentiation capacities of individuals' progenitors. The capacity of cells to proliferate and differentiate is known to decrease with the age of the donor, as well as the time in culture. Likewise, whether this is due to a decrease in the number of MSCs or a change to the existing MSCs is not known. [ citation needed ]

Immunomodulatory effects Edit

MSCs have an effect on innate and specific immune cells. MSCs produce many immunomodulatory molecules including prostaglandin E2 (PGE2), [21] nitric oxide, [22] indoleamine 2,3-dioxygenase (IDO), interleukin 6 (IL-6), and other surface markers such as FasL, [23] PD-L1 and PD-L2. [24]

MSCs have an effect on macrophages, neutrophils, NK cells, mast cells and dendritic cells in innate immunity. MSCs are able to migrate to the site of injury, where they polarize through PGE2 macrophages in M2 phenotype which is characterized by an anti-inflammatory effect. [25] Further, PGE2 inhibits the ability of mast cells to degranulate and produce TNF-α. [26] [27] Proliferation and cytotoxic activity of NK cells is inhibited by PGE2 and IDO. MSCs also reduce the expression of NK cell receptors - NKG2D, NKp44 and NKp30. [28] MSCs inhibit respiratory flare and apoptosis of neutrophils by production of cytokines IL-6 and IL-8. [29] Differentiation and expression of dendritic cell surface markers is inhibited by IL-6 and PGE2 of MSCs. [30] The immunosuppressive effects of MSC also depend on IL-10, but it is not certain whether they produce it alone, or only stimulate other cells to produce it. [31]

MSC expresses the adhesion molecules VCAM-1 and ICAM-1, which allow T-lymphocytes to adhere to their surface. Then MSC can affect them by molecules which have a short half-life and their effect is in the immediate vicinity of the cell. [22] These include nitric oxide, [32] PGE2, HGF, [33] and activation of receptor PD-1. [34] MSCs reduce T cell proliferation between G0 and G1 cell cycle phases [35] and decrease the expression of IFNγ of Th1 cells while increasing the expression of IL-4 of Th2 cells. [36] MSCs also inhibit the proliferation of B-lymphocytes between G0 and G1 cell cycle phases. [34] [37]

Antimicrobial properties Edit

MSCs produce several antimicrobial peptides (AMPs) including human cathelicidin LL-37, [38] β-defensins, [39] lipocalin 2 [40] and hepcidin. [41] These peptides, together with the enzyme indoleamine 2,3-dioxygenase (IDO), are responsible for the broad-spectrum antibacterial activity of MSCs. [42]

Mesenchymal stem cells can be activated and mobilized if needed but their efficiency, in the case of muscle repair for example, is currently quite low. Further studies into the mechanisms of MSC action may provide avenues for increasing their capacity for tissue repair. [43] [44]

Autoimmune disease Edit

Clinical studies investigating the efficacy of mesenchymal stem cells in treating diseases are in preliminary development, particularly for understanding autoimmune diseases, graft versus host disease, Crohn's disease, multiple sclerosis, systemic lupus erythematosus and systemic sclerosis. [45] [46] As of 2014, no high-quality clinical research provides evidence of efficacy, and numerous inconsistencies and problems exist in the research methods. [46]

Other diseases Edit

Many of the early clinical successes using intravenous transplantation came in systemic diseases such as graft versus host disease and sepsis. Direct injection or placement of cells into a site in need of repair may be the preferred method of treatment, as vascular delivery suffers from a "pulmonary first pass effect" where intravenous injected cells are sequestered in the lungs. [47]

Detection Edit

The International Society for Cellular Therapy (ISCT) has proposed a set of standards to define MSCs. A cell can be classified as an MSC if it shows plastic adherent properties under normal culture conditions and has a fibroblast-like morphology. In fact, some argue that MSCs and fibroblasts are functionally identical. [48] Furthermore, MSCs can undergo osteogenic, adipogenic and chondrogenic differentiation ex vivo. The cultured MSCs also express on their surface CD73, CD90 and CD105, while lacking the expression of CD11b, CD14, CD19, CD34, CD45, CD79a and HLA-DR surface markers. [49]

The majority of modern culture techniques still take a colony-forming unit-fibroblasts (CFU-F) approach, where raw unpurified bone marrow or ficoll-purified bone marrow mononuclear cells are plated directly into cell culture plates or flasks. Mesenchymal stem cells, but not red blood cells or haematopoetic progenitors, are adherent to tissue culture plastic within 24 to 48 hours. However, at least one publication has identified a population of non-adherent MSCs that are not obtained by the direct-plating technique. [50]

Other flow cytometry-based methods allow the sorting of bone marrow cells for specific surface markers, such as STRO-1. [51] STRO-1+ cells are generally more homogenous and have higher rates of adherence and higher rates of proliferation, but the exact differences between STRO-1+ cells and MSCs are not clear. [52]

Methods of immunodepletion using such techniques as MACS have also been used in the negative selection of MSCs. [53]

The supplementation of basal media with fetal bovine serum or human platelet lysate is common in MSC culture. Prior to the use of platelet lysates for MSC culture, the pathogen inactivation process is recommended to prevent pathogen transmission. [54]

New research titled Transplantation of human ESC-derived mesenchymal stem cell spheroids ameliorates spontaneous osteoarthritis in rhesus macaques [55] Various chemicals and methods including low level laser irradiation have been used to increase proliferation of stem cell. [56]

In 1924, Russian-born morphologist Alexander A. Maximov (Russian: Александр Александрович Максимов ) used extensive histological findings to identify a singular type of precursor cell within mesenchyme that develops into different types of blood cells. [57]

Scientists Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in the 1960s. [58] [59] An ex vivo assay for examining the clonogenic potential of multipotent marrow cells was later reported in the 1970s by Friedenstein and colleagues. [60] [61] In this assay system, stromal cells were referred to as colony-forming unit-fibroblasts (CFU-f).

The first clinical trials of MSCs were completed in 1995 when a group of 15 patients were injected with cultured MSCs to test the safety of the treatment. Since then, more than 200 clinical trials have been started. However, most are still in the safety stage of testing. [7]

Subsequent experimentation revealed the plasticity of marrow cells and how their fate is determined by environmental cues. Culturing marrow stromal cells in the presence of osteogenic stimuli such as ascorbic acid, inorganic phosphate and dexamethasone could promote their differentiation into osteoblasts. In contrast, the addition of transforming growth factor-beta (TGF-b) could induce chondrogenic markers. [ citation needed ]

More recently, there has been some debate over the use of the term "mesenchymal stem cells" and what constitutes the most scientifically correct meaning for the MSC acronym. Most mesenchymal cell or "MSC" preps only contain a minority fraction of true multipotent stem cells, while most cells are instead stromal in nature. One of the pioneers in the MSC field, Dr. Arnold Caplan, has proposed re-naming MSCs to mean "medicinal signaling cells." [62] Within the stem cell field MSC has most commonly now come to refer to "mesenchymal stromal/stem cells" because of the heterogeneous nature of the cellular preparations.

There is also growing concern about the marketing and injection of MSCs and mesenchymal stem cells into patients by for-profit clinics that lack rigorous data to back up these clinical uses. [63] [64]


Heterogeneity of MSC populations

While the cells fulfilling criteria for MSCs can be harvested from various tissues at all developmental stages (fetal, young, adult and aged) using their plastic adherence property, there are profound differences between obtained MSC populations [22,23]. Bone marrow was historically the first source from which MSCs were obtained, however, over time, there have been reports of the possibility of isolation from other sources of cells with similar properties. Mesenchymal cells are obtained from both tissues and secretions of the adult body, such as adipose tissue, peripheral blood, dental pulp, yellow ligament, menstrual blood, endometrium, milk from mothers, as well as fetal tissues: amniotic fluid, membranes, chorionic villi, placenta, umbilical cord, Wharton jelly, and umbilical cord blood [24�]. MSCs of fetal origin as compared to cells isolated from tissues of adult organisms are characterized by a faster rate of proliferation as well as a greater number of in vitro passages until senescence [38]. However, MSCs derived from bone marrow and adipose tissue are able to create a larger number of CFU-F colonies, which indirectly indicates a higher degree of their stemness. The comparison of gene expression typical for pluripotent cells shows that only in cells isolated from the bone marrow we can observe the expression of the SOX2 gene, the activation of which is associated with the self-renewal process of stem cells as well as with neurogenesis during embryonic development [39]. Discrepancies in the ability of MSCs obtained from various sources to differentiate have also been described. The lack of differentiation of MSCs derived from umbilical cord blood towards adipocytes as well as the greater tendency of MSCs from bone marrow and adipose tissue to differentiate towards osteoblasts were observed [39,40].

In addition to the diverseness observed between MSCs from different sources, there are also differences associated with obtaining them from individual donors. Among the cells isolated from the bone marrow from donors of different ages and sexes, up to 12-fold differences in the rate of their proliferation and osteogenesis were found, combined with a 40-fold difference in the level of bone remodeling marker activity - ALP (alkaline phosphatase). At the same time, no correlations were found resulting from differences in the sex or age of donors [41]. However, the results of studies by other authors indicate that the properties of MSCs isolated from the bone marrow are strongly associated with the age of the donor. Cells collected from older donors are characterized by an increased percentage of apoptotic cells and slower rate of proliferation, which is associated with an increased population doubling time. There is also a weakened ability of MSCs from older donors to differentiate towards osteoblasts [42]. Heo in his work shows the different ability of MSCs to osteogenesis combining it with different levels of DLX5 gene expression (transcription factor with the homeodomain 5 motif) in individual donors, however independent of the type of tissue from which the cells were isolated [39].

The next stage in which we can observe diversity among the MSCs population is in vitro culture. The morphology of cultured cells that originate from the same isolation allows for differentiation into three sub-populations. There are observed spindle-shaped proliferating cells resembling fibroblasts (type I) large, flat cells with a clearly marked cytoskeleton structure, containing a number of granules (type II) and small, round cells with high self-renewal capacity [43,44]. The original hypothesis assumed that all cells that make up the MSCs population are multipotent, and each colony of CFU is capable of differentiating into adipocytes, chondrocytes and osteoblasts, as confirmed by appropriate studies [45]. However, in the literature we can find reports that cell lines derived from a common colony of CFU-F differ in their properties, characterized by uni-, di- or multipotence [46]. Some of the authors showed the division of clonogenic MSCs colonies into as much as eight groups distinct in their potential for differentiation. At the same time, it is suggested that there is a hierarchy within which cells subordinate to each other are increasingly directed towards osteo- chondro- or adipocytes and gradually lose their multipotential properties to di- and unipotential ones. This transformation may also be associated with a decrease in the rate of cell proliferation and the level of CD146 protein expression (CD cluster of differentiation) - proposed as a marker of multipotency [47].


Company Outline

Mission

We provide stem cell application technologies to realize efficient drug discovery. Furthermore, by continuously advancing and improving our technologies, we aim to contribute to the development of feasible regenerative medicine technologies.

Objectives

  • We develop and supply high quality cell-based products that exceed the requirements demanded by drug discovery assays.
  • We promote technology integration and development through collaboration with companies aiming at the development of cell-related fields and the creation of businesses.
Head Office

OFFICE-ONE Shijo Karasuma 11F, 480, Niwatoriboko-cho, Shimogyo-ku,
Kyoto 600-8491 Japan

Mikuruma Office

209 Creation Core Kyoto Mikuruma, 448-5, Kajii-cho, Kamigyo-ku,
Kyoto 602-0841 Japan

Kensuke Kato, PhD. is the founding CEO of SCAD. From his initial experiences at the Agency of Industrial Science and Technology (currently AIST) and Hitachi Mechanical Engineering Research Laboratory, Dr. Kato has accumulated more than 20 years of experience in product and business development in high-technology fields including life science. Through the establishment of his own start-up backed by the Tokyo Institute of Technology in 2008, he supported a wide range of companies—from electrical and material manufacturers to public research institutions—with the formulation and execution of their new business development strategies. In 2014, Dr. Kato established the Stem Cell & Device Laboratory (SCAD) in Kyoto, Japan.

He specialized in business strategies for new technology commercialization at the Tokyo Institute of Technology (PhD., Management of Technology). He is a visiting professor at Ritsumeikan Asia Pacific University (APU), College of International Management and a part-time assistant professor at the University of Tokyo, Graduate School of Frontier Science. He also serves as Director of Japan Society for Research Policy and Innovation Management (JSRPIM).

Chief Advisor
Norio Nakatsuji

Prof. Nakatsuji is considered one of the pioneering stem cell researchers in Japan. After graduating from Kyoto University’s Faculty of Science with a PhD. in 1977, Prof. Nakatsuji conducted several research stays in the United States and the United Kingdom. During his professorial careers at the National Institute of Genetics and at Kyoto University’s Institute for Frontier Medical Sciences, Prof. Nakatsuji carried out the pioneering development and differentiation of diverse cell types, including embryonic stem (ES) cells, germ cells, and neurons. In fact, he led the Kyoto University team that established the first human ES cell line in Japan and distributed them to other scientists free of charge.

In 2003, Prof. Nakatsuji founded the university-originated start-up company Reprocell, which accomplished a successful IPO in 2013. From 2003 to 2007, he served as the Director of Kyoto University’s Institute for Frontier Medical Sciences. In 2007, he founded Kyoto University’s Institute for Integrated Cell-Material Sciences, an institute which advances cross-disciplinary research and technological innovation based on cell biology, chemistry and physics. In 2014, he also established the Kyoto Stem Cell Innovation, Inc., and currently serves as its CEO. Prof. Nakatsuji is also the Director General of Nakatsuji Foresight Foundation, which is a non-profit organization established to support society and young leaders of the next generation by advancing programs relating to education, science and technology.

Mr. Date is a professional manager of a high-tech startup company with a background in finance. After graduating from university, he joined the Long-Term Credit Bank of Japan. At the bank, he conducted industry researches on the automobile industry and engaged in consulting business for auto and auto parts companies. He studied Latin American Economics and Politics at UC San Diego, and then worked in Mexico City and New York. In New York, he conducted project financing in Latin American countries and financing for government agencies in cooperation with World Bank Group.

At Shinsei Bank, he played a major role of launching investment banking business and left the bank in 2006. Since then, he continues to support various type of high-tech startups. He joined SCAD in August 2020. Prior to joining SCAD, he was the CFO of Momotaro Gene Inc. for four years.

Bachelor of Law, Kyoto University. Completed Management of Technology Program of The University of Tokyo, Graduate School of Engineering.

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Stem Cell & Device Laboratory, Inc. (SCAD) All Rights Reserved.


Full name for stem cells - Biology

Adult Stem Cells (ASCs):

ASCs are undifferentiated cells found living within specific differentiated tissues in our bodies that can renew themselves or generate new cells that can replenish dead or damaged tissue.  You may also see the term “somatic stem cell” used to refer to adult stem cells.  The term “somatic” refers to non-reproductive cells in the body (eggs or sperm).  ASCs are typically scarce in native tissues which have rendered them difficult to study and extract for research purposes.

Resident in most tissues of the human body, discrete populations of ASCs generate cells to replace those that are lost through normal repair, disease, or injury. ASCs are found throughout ones lifetime in tissues such as the umbilical cord, placenta, bone marrow, muscle, brain, fat tissue, skin, gut, etc.   The first ASCs were extracted and used for blood production in 1948.  This procedure was expanded in 1968 when the first adult bone marrow cells were used in clinical therapies for blood disease. 

Studies proving the specificity of developing ASCs are controversial some showing that ASCs can only generate the cell types of their resident tissue whereas others have shown that ASCs may be able to generate other tissue types than those they reside in.  More studies are necessary to confirm the dispute.

Types of Adult Stem Cells:

    • Hematopoietic Stem Cells (Blood Stem Cells)
    • Mesenchymal Stem Cells
    • Neural Stem Cells
    • Epithelial Stem Cells
    • Skin Stem Cells

    Embryonic Stem Cells (ESCs):

    During days 3-5 following fertilization and prior to implantation, the embryo (at this stage, called a blastocyst), contains an inner cell mass that is capable of generating all the specialized tissues that make up the human body.  ESCs are derived from the inner cell mass of an embryo that has been fertilized in vitro and donated for research purposes following informed consent.  ESCs are not derived from eggs fertilized in a woman’s body. 

    These pluripotent stem cells have the potential to become almost any cell type and are only found during the first stages of development.  Scientists hope to understand how these cells differentiate during development.  As we begin to understand these developmental processes we may be able to apply them to stem cells grown in vitro and potentially regrow cells such as nerve, skin, intestine, liver, etc for transplantation. 

    Induced Pluripotent Stem Cells (iPSCs)

    Induced pluripotent stem cells are stem cells that are created in the laboratory, a happy medium between adult stem cells and embryonic stem cells.  iPSCs are created through the introduction of embryonic genes into a somatic cell (a skin cell for example) that cause it to revert back to a “stem cell like” state.  These cells, like ESCs are considered pluripotent Discovered in 2007, this method of genetic reprogramming to create embryonic like cells, is novel and needs many more years of research before use in clinical therapies.  


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    Abstract

    Mesenchymal stem cells (MSCs) have gained widespread use in regenerative medicine due to their demonstrated efficacy in a broad range of experimental animal models of disease and their excellent safety profile in human clinical trials. Outcomes from these studies suggest that MSCs achieve therapeutic effects in vivo in nonhomologous applications predominantly by paracrine action. This paracrine-centric viewpoint has become widely entrenched in the field, and has spurred a campaign to rename MSCs as “medicinal signaling cells” to better reflect this mode of action. In this Commentary, we argue that the paracrine-centric viewpoint and proposed name change ignores a wealth of old and new data that unequivocally demonstrate the stem cell nature of MSCs, and also overlooks a large effort to exploit homologous applications of MSCs in human clinical trials. Furthermore, we offer evidence that a stem cell-centric viewpoint of MSCs provides a comprehensive understanding of MSC biology that encompasses their paracrine activity, and provides a better foundation to develop metrics that quantify the biological potency of MSC batches for both homologous and nonhomologous clinical applications. S tem C ells 201836:7–10

    In a recently published perspective, Dr. Arnold Caplan strongly advocates for adopting the term “medicinal signaling cells” to replace “mesenchymal stem cells” (MSCs) based on the assertion that the latter are “immunomodulatory and trophic (regenerative) meaning that these cells make therapeutic drugs in situ that are medicinal” 1 . Caplan further contends that “MSCs do not function in the body as progenitors for tissues, neither in the normal steady-state nor in disease or injury circumstances they are not stem cells”. This statement overlooks decades of scientific evidence that unequivocally demonstrates the stem cell nature of the MSC. In deference to Dr. Caplan, his statement echoes a long-held opinion that stem/progenitor properties of MSCs are dispensable for their nonhomologous therapeutic efficacy in human patients. However, we argue that this paracrine-centric viewpoint of the MSC is grossly oversimplified, and obfuscates a growing body of work indicating that stem/progenitor and paracrine functions of MSCs are interdependent.

    The paracrine-centric viewpoint of MSCs has evolved from studies conducted over the past decade showing MSCs secrete a plethora of paracrine acting factors 2 and RNA/protein laden microvesicles 3 , that these biologics contribute directly to the therapeutic potency of MSCs in preclinical animal models of disease, and that MSCs demonstrate measurable effects with respect to their nonhomologous use in human patients despite their short-lived survival in vivo 1, 4 . Therefore, empirical evidence in support of this hypothesis is compelling, but the viewpoint also promulgates that stem/progenitors functions are unnecessary and needless in determining the potency of these MSC-based therapies. As detailed below, the proposed stem cell-centric viewpoint encompasses all aspects of MSC biology, their homologous and nonhomologous application in clinical therapy, and provides a more robust foundation for developing metrics that predict clinical efficacy.

    Over five decades ago Alexander Friedenstein and colleagues were the first to identify a novel stem cell in bone marrow by demonstrating its capacity to generate hematopoiesis sustaining heterotopic osseous tissue when serially passed through successive transplant recipients 5, 6 . Numerous studies have since confirmed that this stem cell population, now referred to as MSCs, skeletal stem cells or mesenchymal stromal cells, is capable of transferring the hematopoietic environment to heterotopic sites in vivo 7, 8 and differentiating into connective tissue lineages in vitro according to a heirarchical model 9, 10 . Fate mapping studies have further identified Leptin receptor (LEPR) 11 , Nestin 8 , and Alpha V integrin 12 expressing subpopulations (and others) that function as a resevior of bone, fat, cartilage, and/or stroma in adult bone marrow, and also represent to varying degrees the source of cytokines that regulate hematopoietic stem cell (HSC) self-maintenance and retention in the perivascular marrow niche 13 . Moreover, Muguruma et al. 14 demonstrated that human MSCs transplanted intramedullary reconstituted a functional hematopoietic niche and differentiated into pericytes and bone lining osteoblasts and osteocytes. Related studies have further shown that the frequency and function of MSCs in vivo are significantly influenced by pathological states of the host. For example, Bianco et al. 15 noted changes in the density and distribution of MSCs in the bone marrow of patients with hematological and bone diseases. On this note, recent studies have linked sympathetic neuropathy and expansion of leukemia-supportive MSCs in bone marrow with leukemia progression in an animal model of acute myeloid leukemia (AML) 16 , and altered interleukin 10 production by MSCs with disease evolution and therapy resistance in human AML patients 17 . Additionally, systemic energy imbalances resulting from high fat diet feeding have been shown to skew bifurcation of LEPR expressing MSCs toward adipogenesis resulting in skeletal involution and fattening of bone marrow, and MSC-specific deletion of LEPR reduces the abarrent bone phenotype in response to high fat diet feeding 18 . Furthermore, dysregulated expression of CXCL12 in niche resident Nestin-expressing MSCs has also been linked to impaired HSC mobilization in diabetes patients 19 . In contrast, peripheral pericytes were shown to not contribute to formation of new skeletal and fat tissue in adult mice under homeostatic conditions and in response to injury 20 . Together, these studies demonstrate that MSCs function in vivo as stem/progentiors, and that their dysfunction manifests as changes in skeletal homeostasis and hematopoiesis and may contribute directly to disease pathophysiology.

    Emerging data further indicate that paracrine effector functions, such as those highlighted by Caplan and exploited in MSC-based clinical trials, are closely coupled to stem/progentior activities. For example, MSCs are widely exploited for their pro-angiogenic activity and preconditioning regimens that enhance angiogenic potential also positively impact cell proliferation, survival, and self-renewal 21-23 . Additionally, inteferon gamma licenses the paracrine-based immuno-modulatory activity of MSCs but inhibits cell growth 24, 25 , alters responses to adipogenic and osteogenic stimuli in vitro, and rescues osteopororsis while preventing marrow fat accumulation in ovariectomized mice 26, 27 . Conversely, commitment of human MSCs to the osteogenic lineage coincides with activation of the kynurenine pathway resulting in a transient burst of inteferon gamma secretion 28 . Furthermore, exposure to fluid frictional forces that effect cellular differentiation also upregulate expression of immuno-modulatory effector proteins in MSCs and enhances their anti-inflammatory activity in a rat model of traumatic brain injury 29 . Similarly, Lee et al. 30 demonstrated that age, gender, and skeletal height of human donors had a predictable influence on the differentiation potential (stem cell function) and anti-inflammatory activity (paracrine function) of MSCs. For example, MSCs from tall donors were shown to be highly osteogenic and less anti-inflammatory where those from female donors or those of short stature were more anti-inflammatory and less osteogenic.

    Our own recent work in MSCs demonstrates a direct mechanistic link between stem/progenitor and paracrine effector functions (Fig. 1). For example, in a comparative anlaysis of multiple human MSC populations we found that expressed levels of the transcription factor TWIST1 correlated with population growth rates, colony forming unit-fibroblast activity, tri-lineage differentiation potential, and angiogenin gene expression levels. Moreover, silencing of TWIST1 conferred onto these cells an anti-inflammatory and immune-modulatory phenotype at the expense of angiogenic activity, and also induced competence to undergo stimulus driven tri-lineage differentiation 25 . Mechanistically, TWIST1 was shown to be induced by fibroblast growth factor 2 and inhibited by interferon gamma treatments. Importantly, TWIST1 expression levels predicted the biological potency of human MSC donor populations in cell-based assays and therapeutic efficacy in an animal model of acute lung injury 25, 31 .

    Venn diagram showing relationship between mesenchymal stem cells (MSCs) and medicinal signaling cells. Medicinal signaling cells by definition represent a subset of MSCs. Paracrine functions ascribed to medicinal signaling cells are encompassed by MSCs, which also possess stem/progenitor (stemness, hematopoiesis, angiogenesis) and skeletogenic properties. Importantly, stem/progenitor and paracrine functions are coordinately regulated in MSCs by TWIST1 mRNA levels (green gradient), and are specified by a hierarchical process. MSCs are beneficial for homologous and nonhomologous clinical applications while medicinal signaling cells are used exclusively in nonhomologous applications.

    Based on these findings, we submit that a stem cell-centric framework more adequately describes the biological activity of MSCs under normal physiological and pathologic conditions, and can be exploited to develop metrics that predict differences in stem/progenitor and paracrine effector functions rather than just a single function (Table 1 Fig. 1). As our own work has shown, such metrics have the potential to match the biological potency of donor populations with specific disease indications to deliver more reliable and efficacious homologous and nonhomologous MSC-based therapies. Consequently, we strongly urge the community to not adopt the term “medicinal signaling cells” as this terminology describes only one salient feature of MSCs and their perceived mode of action following their nonhomologous use in human patients. As outlined above, the term provides an incomplete description of the nature and function of MSCs. Indeed, changing the name from mesenchymal stem cells to medicinal signaling cells deflects from the critical issues at hand, which are to gain an in depth knowledge of MSC biology in order to exploit their inherent physiological functions to develop highly efficacious and reliable cell-based therapies.

    Function/Application Mesenchymal stem cells vs. Medicinal signaling cells
    Anatomical location Encompasses skeletal stem cells, pericytes, and culture expanded cells. Refers only to culture expanded cells.
    Self-renewal Can serially regenerate heterotopic osseous tissue. Are not stem cells so do not self-renew.
    Biological activity Encompasses stem/progenitor and paracrine (medicinal signaling) functions, which are mechanistically linked and coordinately regulated. Encompasses only medicinal signaling (paracrine) activities, which are independent of stem/progenitor functions.
    Interpopulation and intrapopulation heterogeneity can be modeled via a hierarchical process. Heterogeneity lies in medicinal signaling (paracrine) activity only, and is largely extrinsically regulated.
    Clinical application Explains homologous and nonhomologous use. Resolves skeletogenic, angiogenic, and anti-inflammatory/immuno-modulatory activities. Explains only nonhomologous use. Medicinal signaling (paracrine) functions are not resolved.
    Donor populations not predicted to possess equal potency for a given disease indications One donor population is used to treat mechanistically diverse pathologies.
    Offers means to match specific donor populations to specific disease indications. Clinical isolates need to be “tuned” or “primed” to enhance therapeutic potency.
    Offers means to tailor cGMP manufacturing regimens to produce MSC batches of known potency. Similar manufacturing regimens are used for all clinical indications.


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