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The Stem Cell Theory of Cancer | Ludwig Center | Stanford …

By Stem Cell Medicine

Research has shown that cancer cells are not all the same. Within a malignant tumor or among the circulating cancerous cells of a leukemia, there can be a variety of types of cells. The stem cell theory of cancer proposes that among all cancerous cells, a few act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells normally renew and sustain our organs and tissues. In this view, cancer cells that are not stem cells can cause problems, but they cannot sustain an attack on our bodies over the long term.

The idea that cancer is primarily driven by a smaller population of stem cells has important implications. For instance, many new anti-cancer therapies are evaluated based on their ability to shrink tumors, but if the therapies are not killing the cancer stem cells, the tumor will soon grow back (often with a vexing resistance to the previously used therapy). An analogy would be a weeding technique that is evaluated based on how low it can chop the weed stalksbut no matter how low the weeks are cut, if the roots arent taken out, the weeds will just grow back.

Another important implication is that it is the cancer stem cells that give rise to metastases (when cancer travels from one part of the body to another) and can also act as a reservoir of cancer cells that may cause a relapse after surgery, radiation or chemotherapy has eliminated all observable signs of a cancer.

One component of the cancer stem cell theory concerns how cancers arise. In order for a cell to become cancerous, it must undergo a significant number of essential changes in the DNA sequences that regulate the cell. Conventional cancer theory is that any cell in the body can undergo these changes and become a cancerous outlaw. But researchers at the Ludwig Center observe that our normal stem cells are the only cells that reproduce themselves and are therefore around long enough to accumulate all the necessary changes to produce cancer. The theory, therefore, is that cancer stem cells arise out of normal stem cells or the precursor cells that normal stem cells produce.

Thus, another important implication of the cancer stem cell theory is that cancer stem cells are closely related to normal stem cells and will share many of the behaviors and features of those normal stem cells. The other cancer cells produced by cancer stem cells should follow many of the rules observed by daughter cells in normal tissues. Some researchers say that cancerous cells are like a caricature of normal cells: they display many of the same features as normal tissues, but in a distorted way. If this is true, then we can use what we know about normal stem cells to identify and attack cancer stem cells and the malignant cells they produce. One recent success illustrating this approach is research on anti-CD47 therapy.

Next Section >> Case Study: Leukemia

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The Stem Cell Theory of Cancer | Ludwig Center | Stanford ...

IPSCjun19 Induced Pluripotent Stem Cells: differentiation …

By Induced Pluripotent Stem Cells

ABOUT THE COURSE

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This a hands-on practical course on Induced pluripotent stem cells (iPSCs) differentiation into hepatocytes.iPSCs provide an inexhaustible source of cells, which can bedifferentiated into any lineage. iPSCs are generated from normal and disease adult cells (such asblood cells or skin cells) via reprogramming using a defined set of transcription factors (Oct4, Sox2, c-Myc, Kif4).Hepatocytes are liver cells, which make up 70-85 % of the liver mass. These cells are involved inprocesses such as protein synthesis, carbohydrate metabolism and detoxification, which areassociated with many diseases. iPSC derived hepatocytes can be used for basic liver research such asunderstanding liver development and cell biology, as well as for disease modelling and toxicity screening.

In this Induced pluripotent stem cells (iPSCs) differentiation into hepatocytes courses:

1. Participants will be introduced to the background, maintenance and applications of iPSC technology. 2. During the hands-on practical, participants will learn how to derive hepatocytes from human iPSCs. 3. Participants will take part in interactive tutorials, Q&A clinics, and panel discussions, with leading scientistswho will answer any questions you may have about your individual projects, to help you to avoid the commonpitfalls of using iPSCs in your experiments.

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OTHER INFORMATION

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LEARNINGOBJECTIVESOF THIS IPSCs DIFFERENTIATION INTO HEPATOCYTE COURSE:

1. To understand the history, manipulation and use of iPSCs 2. To gain knowledge of hepatocyte structure and function 3. Learn how to differentiate human iPSCs into hepatocytes 4. To gain knowledge about the use of differentiated hepatocytes in both basic research anddisease modelling

courses@cambioscience.com

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PROGRAMME

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INSTRUCTORS

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Professor David Hay

MRC Centre for Regenerative Medicine, University of Edinburgh

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David Hay is Professor of Tissue Engineering at the University of Edinburgh. David has worked in the field of stem cell biology and differentiation for over fifteen years. David andhis team have highlighted the important role that pluripotent stem cells have to play inmodelling human liver biology in a dish and supporting failing liver function in vivo. Theimpact of this work has led to a number of peer reviewed publications, regular appearancesat high profile conferences and three start-up companies.

Dr Rute Tomaz

Wellcome-MRC Cambridge,Stem Cell Institute and the Department of Surgery

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Dr Rute Tomaz is a postdoc research associate at Dr Ludovic Valliers lab, part of theWellcome-MRC Cambridge Stem Cell Institute and the Department of Surgery. Since joiningthe lab in 2016, her research has focused on the developing novel methods fordifferentiation and maturation of hepatocytes from human pluripotent stem cells forsubsequent applications such as disease modelling and drug screening. Prior to joining thislab, Rute did her PhD at Imperial College London where she studied gene regulationmechanisms in early cell fate choices using mouse embryonic stem cells as a model.

Dr Daniel Ortmann

Wellcome-MRC Cambridge, Stem Cell Institute and the Department of Surgery

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Dr Florian Merkle

Principal Investigator, Metabolic Research Laboratories, University of Cambridge

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The Merkle laboratory studies the molecular and cellular basis of human diseases using a combination of human cellular models and animal models. They have a particular interest in obesity, which leads to millions of premature deaths each year, lacks broadly effective treatments, and is associated with the aberrant function of specific neuron types in the hypothalamus. The lab developed methods to differentiate human pluripotent stem cells (hPSCs) into functional hypothalamic cell types in culture, enabling us to study their function in health and obesity using a range of cutting-edge techniques including genome engineering, single-cell transcriptomics, quantitative peptidomics, high content imaging, calcium imaging, and xenotransplantation. Research in the Merkle laboratory revolves around three areas: 1) Basic biology of human hypothalamic neurons 2) Genetic and environmental contributions to obesity 3) Translation and in vivo models Dr. Merkle is affiliated to the Cambridge Stem Cell Institute,collaborates with the Wellcome Sanger Institute and EBI in the context of his single-cell RNAseq work, and was recently awarded the prestigious Sir Henry Dale fellowship, during which he will use gene editing to explore how obesity-associated mutations alter cellular phenotypes.

Dr Annika Asplund

Senior Scientist, Takara Bio

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Annika Asplund is a Senior Research Scientist at Takara Bio Europe, AB in Sweden. She completed her PhD in molecular medicine within the field of cardiovascular prevention at Gothenburg University, Sweden. In 2012 she joined Takara Bio, focusing on hepatocyte differentiation and maturation from human pluripotent stem cells. Annika has extensive experience in protocol development for hepatocyte differentiation and characterization as well as dissociation and cryopreservation and contributed to the development of several innovative solutions offered by Takara Bio. She is committed to improving Takara Bios hepatocyte solutions and to helping customers succeeding with their hepatocyte related experiments.

Dr Johannes Elvin

Senior Production and Service Specialist, Takara Bio

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Johannes Elvin is a Senior Production and Service Specialist and joined Takara Bio Europe AB in 2018. He did his PhD at Gothenburg University in renal medicine and transitioned into the field of diabetes and obesity during his postdoc. He has been working extensively with in vitro cell culture, lentiviral transduction and protein expression modification. He is now handling and running service projects aimed at reprogramming somatic cells into pluripotent stem cells.

Dr Christian Andersson

Product Development Manager, Takara Bio

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Christian Andersson is a senior scientist and Product Development Manager at Takara Bio Europe, AB. He has extensive experience of culturing and differentiate stem cells into preferred cell types, where his field of expertise are Beta Cells. He has worked in project team to commercialize, market and promote Takara Bios stem cell portfolio all over the world. He is part of the companys stem cell strategy and marketing team, defining stem cell projects, marketing approaches, and business development opportunities.

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REGISTRATION DETAILS

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17 SPACES AVAILABLE

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With this course you get our exclusive CamBioScience membership for free and receive an automatic 10% discount on your registration fee.

* These fees include your 10% discount.

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To register, please click below and fill in the registration form. You will then receive an email confirmation in which you will be able to choose a payment method (pay by card online, or receive an invoice to process payment by bank transfer).

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PARTNERS

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IPSCjun19 Induced Pluripotent Stem Cells: differentiation ...

‘Stem cell’ therapies offered at private clinics need to …

By Stem Cell Clinics

Dr. Mark Berman injects a patient with a solution he says is rich in adult stem cells at his practice in Beverly Hills, Calif., in this December 2014 file photo.

This is an excerpt from Second Opinion, a weekly roundup of eclectic and under-the-radar health and medical science news emailed to subscribers every Saturday morning. If you haven't subscribed yet, you can do that by clicking here.

Canada's direct-to-consumer cell therapyindustry is thriving.

Across the country, private clinics continue to sell expensive procedures advertised as a form of "regenerative medicine."

The clinics use what they claim are stem cellsthat are siphoned from a patient's bone marrow or fat tissue and injected or given intravenously to treat a range of conditions including joint pain, multiple sclerosisand nerve disorders.

There is a lack of clinical trial evidence to determine whether the procedures are safe and effective. And there has been a long-running debate about whether they're legal.

This week Health Canada issued a public policy position on that point.

"All cell therapies are considered drugs under the Food and Drugs Act. This means that they must be authorized by Health Canada to ensure that they are safe and effective before they can be offered to Canadians," Health Canada said in a news release.

That policy statement confirms that cell therapies are not legal in Canada unless they've been formally approved as drugs, after going through a rigorous review. And so far Health Canada has not approved any of the direct-to-consumer treatments.

Health Canada also warned Canadians about potential safety risks.

"Unauthorized treatments have not been proven to be safe or effective and may cause life-threatening or life-altering risks, such as serious infections."

If these procedures are not approved, and might not be safe, are they still happening? The answer is yes.

Almost a dozen clinics across Canada confirmed to CBC News that they are still doing the procedures, with prices quoted as high as $15,000. Ten other clinics that advertised the procedures on their websitecould not be reached for comment.

Health Canada has been in touch with some of the clinics to inquire about their practice, but so far the agency has nottaken any action to stop clinics from doing the autologous procedures. ("Autologous" means the patient's own cells or tissue are being used.)

That's puzzling to University of Minnesota researcher Leigh Turner, who provided his research notes to Health Canada months agoshowing that there were 43clinics in Canada doing the procedures. Turner's findings were published last September.

"It's like Health Canada is saying, 'We know these business aren't complying with Canadian law, and even in our latest document we're confirming that. Nonetheless, we're going to stand here on the sidelines with our hands in our pockets and not doing anything about it.' And that, to me, is the problem," Turner said.

"I don't understand why it's not more of a priority for Health Canada."

Health Canada spokesperson Andr Gagnon told CBC News in an email that the agency is "currently working to bring clinics into compliance with the applicable regulatory framework."

"This will include requesting clinics to stop selling and advertising cell therapy products that do not meet the applicable requirements."

Health Canada did not indicate when it would take that action.

Turner said it's long overdue.

"We're talking about a nationwide phenomenon right now that has received national news coverage," he said. "There's a tremendous amount of empirical information. Health Canada has interacted with people willing to provide more information. Years have ticked by.That's enough time for Health Canada to take meaningful action."

One Alberta clinic announced on its website that it has officially stopped doing the procedures because they fall into a regulatory grey area.

"It was a decision we made and it was our decision alone," said Joe Burnham, regulatory manager at the Capri Clinic in Lacombe, Alta. The clinic performed about 1,500 procedures before deciding to stop in March. But patients are still calling.

"That's 80 per cent of our calls to this day. When are you guys up and running?"

Burnham said his clinic is investigating how to comply with Health Canada's regulations, but it's not yet clearhow that can be done.

"Doctors that are doing procedures aren't drug companies. And the minute you call a procedure a drug, even if you have a regulatory right to, it turns doctors into drug manufacturers. That's the confusion," Burnham said.

Health Canada acknowledged that challenge, telling CBC News: "There is uncertainty surrounding the practical means of meeting federal product safety regulatory requirements for the sale of cell therapies that aren't mass produced, especially once initial clinical trials are completed.

"Health Canada is working to identify and overcome challenges specific to meeting regulatory requirements for the manufacturing and sale of autologous cell therapy products, including those prepared at the bedside."

Despite the claims from clinics that they areextracting stem cells,the clinicsdon't examine the fluid to determine what sorts of cells and other cellular products it contains.

And scientists point out that it is unlikely to contain true stem cells, which are cells that can transform into any tissue in the body. The extract from bone marrow and fat tissue containsanother type of cellsthat wereoriginally called "mesenchymal stem cells."But scientists now say that name is inaccurate and confusing.

In a commentary in Nature, with the title "Clear up this stem cell mess," Turner and some colleagues explained how the science has evolved since the cells in question were first described and named 25 years ago.

"They don't behave like stem cells," Michael Rudnicki, stem cell scientist at the Ottawa Hospital Research Institute, told CBC News last September when we first wrote about the name controversy. "None of the criteria we use to define stem cells are present in this population."

"There are clinical trials exploring their ability to modulate the immune system,but it's not a regenerative phenomenon," said Rudnicki, adding that most researchers in the scientific community have abandoned the term "mesenchymal stem cells" and instead call them "mesenchymal stromal cells."

By continuing to use the term "stem cell" for the fluid that is taken from a patient's bone marrow and fat, there is concern that patients will be misled into believing the therapies are able to regenerate bone and tissue, which has not been proven.

To read the entire Second Opinion newsletter every Saturday morning,pleasesubscribe.

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'Stem cell' therapies offered at private clinics need to ...

Embryonic Stem Cell – an overview | ScienceDirect Topics

By Embryonic Stem Cells

Charles E. Murry, ... Lior Gepstein, in Heart Development and Regeneration, 2010

Embryonic stem cells (ESCs) are pluripotent cells derived from the inner cell mass of blastocyst-stage embryos. Mouse embryonic stem cells (mESCs) have been studied for several decades, and have provided major advances in our understanding of developmental biology and gene function in the adult organism. The single greatest application of mouse embryonic stem cells has been in studies of gene function through homologous recombination (knockout or knockin strategies). These studies were made possible by the remarkable ability of genetically-modified embryonic stem cells to incorporate into all tissues of a developing mouse after injection into a blastocyst, followed by the ability of resulting chimeric mice to pass the genetic modification via the germline. Embryonic stem cells have also been useful tools for understanding molecular events controlling differentiation into the early germ layers and more distal branches of the developmental tree. Over the last 15 years an increasing number of groups have become interested in the use of mouse embryonic stem cells as a cell source to treat murine models of cell deficiency.

Research in this area gained worldwide prominence, extending far beyond the usual scientific community, when Jamie Thomsons group at the University of Wisconsin reported developing the first lines of human embryonic stem cells (hESCs) in 1998 (Thomson et al., 1998b). A veterinary pathologist with an interest in early human development, Thomson had honed his skills by first deriving lines of embryonic stem cells from nonhuman primates (marmosets and rhesus monkeys) (Thomson et al., 1995, 1996). To derive human embryonic stem cells, Thomsons group worked with blastocysts donated by fertility clinic patients, who no longer intended to use these spare embryos for reproductive purposes (these blastocyts are commonly discarded if they are not to be used for reproductive purposes). The embryos were 5 days post-in vitro fertilization, and were at the blastocyst stage, a hollow ball of 150 cells surrounded by a carbohydrate-rich zona pellucida. Blastocysts contain a rim of trophoectoderm cells, which gives rise to the placenta and amniotic membranes, and an inner cell mass, which gives rise to the embryo proper. (By way of comparison, a 5-day-old embryo derived from traditional fertilization is at a preimplantation stage, still residing in the fallopian tube). To derive the human embryonic stem cells, Thomsons group enzymatically digested the zona pellucida and removed the trophoectoderm using antibodies and complement (immunosurgery) (Fig. 1), leaving the inner cell mass intact. The inner cell mass was placed into a culture system, using feeder layers of mouse embryonic fibroblasts to provide a still-unknown set of factors that had maintained other primate embryonic stem cells in the undifferentiated state. The human cells thrived in this environment, growing for hundreds of population doublings while still expressing molecular markers of pluripotency and retaining the ability to differentiate into a wide variety of cell types in vitro. Importantly, after implantation into immuno-tolerant mice, human embryonic stem cells formed teratomas, tumors comprised of cells from endoderm, mesoderm and ectoderm. At present, teratoma formation represents the most definitive evidence for human embryonic stem cell potency, since human blastocyst injection is widely-considered to be unethical. Since this original publication, over 100 lines of human embryonic stem cells have been derived worldwide by similar techniques (Cowan et al., 2004; Musri et al., 2006).

Figure 1. Embryonic stem cell derivation. Cells in the inner cell mass (ICM) of pre-implantation embryos are isolated by the removal of the trophectoderm by immunosurgery (antibody and complement-mediated lysis). To maintain cells in the undifferentiated state, inner cell mass cells are plated on a mouse embryonic fibroblasts feeder layer. These undifferentiated cells can be induced to differentiate into cells from the different germ layers.

It is important to consider the scientific context in which this advancement came. The late-1990s and early-2000s had yielded a number of other major scientific advancements, including sequencing of the human genome (Lander et al., 2001) and cloning of the first mammal, Dolly the sheep (Campbell et al., 1996). Thus, within a few short years, science had delivered the genetic blueprint of humanity, techniques to completely dedifferentiate a cell and grow a new mammal from it, and early human cells that could develop into any tissue. Understandably, this triggered a response that extended beyond the scientific community and into the lay press, public coffeehouses, churches and political forums. Most countries are still debating the extent to which human embryonic stem cell research should be regulated, and public policies range widely, from governmental encouragement, to legal restrictions, to outright bans. While not the topic of this chapter, we would encourage all readers to explore the ethics and policy implications of human embryonic stem cell research, and we refer those interested to references (Green, 2001; Daley et al., 2007; Sugarman, 2007) for in-depth analyses.

Human embryonic stem cells share many similarities with their murine counterparts, but they also have several important differences. Like mouse embryonic stem cells, human embryonic stem cells can divide extensively without telomere shortening and by this criterion appear to be immortal. Although there is not complete overlap with mouse embryonic stem cells, human embryonic stem cells express surface markers characteristic of pluripotent cells. Additionally, both embryonic stem cell types express transcription factors required for pluripotency, including Oct4 and Nanog. In mouse embryonic stem cells, the cytokine leukemia inhibitory factor (LIF) is necessary to maintain cells in their pluripotent state (Williams et al., 1988; Pease and Williams, 1990). In contrast, human embryonic stem cells will differentiate in the presence of LIF (Zaehres et al., 2005) and require FGF for pluripotency. Bone morphogenetic proteins (BMPs) contribute to the maintenance of pluripotency of mouse embryonic stem cells (Ying et al., 2003), whereas they induce trophoblast differentiation in human embryonic stem cells (Xu et al., 2002). The optimal conditions to maintain human embryonic stem cells in the pluripotent state are still being worked out. For this reason, most investigators currently use either mouse embryonic fibroblast feeder layers, or medium conditioned by these cells (supplemented with bFGF) (Xu et al., 2001) for growth and maintenance of undifferentiated human embryonic stem cells.

Mouse embryonic stem cells typically grow as tight clusters and show a high plating efficiency after dissociation to single cells. These characteristics facilitate their low-density plating and subsequent isolation of subclones. In contrast, undifferentiated human embryonic stem cells typically grow as flat two-dimensional colonies, which are passaged by forming smaller clumps (either through partial enzymatic digestion or mechanical dissociation) and allowing them to expand. Furthermore, the establishment of clonal lines is more difficult with human embryonic stem cells, because they do not tolerate single cell dispersion as well as mouse embryonic stem cells. Human embryonic stem cells must be karyotyped regularly to screen for chromosomal abnormalities, such as trisomies 12 and 22, as well as several translocation variants (reviewed in Baker et al., 2007) that can accumulate with time in culture. Time in culture can also affect the differentiation efficiency of some cell types, including cardiomyocytes. It is likely that these difficulties reflect our still-imperfect ability to culture the cells, which may improve as the community gains experience.

The difference between mouse embryonic stem cells and human embryonic stem cells has been assumed to relate to species differences in signaling requirements for pluripotency. Recently, however, two groups isolated pluripotent cells from postimplantation stage mouse epiblasts (Brons et al., 2007; Tesar et al., 2007). These epiSCs do not use the LIF/STAT3 pathway for maintaining pluripotency, but instead use pathways initiated by activin/nodal and FGF, similar to human embryonic stem cells. Interestingly, while epiSCs formed teratomas after injection into host mice, they did not generate chimeric embryos after blastocyst injection. The similarity of mouse epiSCs to human embryonic stem cells has raised the possibility that signaling pathways between species are actually conserved, with the difference being that human embryonic stem cells represent a later developmental stage than mouse embryonic stem cells.

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Embryonic Stem Cell - an overview | ScienceDirect Topics

LifeCell – India’s First and Largest Stem Cell Bank

By Stem Cell Doctors

LifeCell is a research-intensive premier biotech company driven by the power of medical science and innovation for 14 years. As an extension of our commitment towards the healthcare sector, LifeCell has expanded its newest division, Biologics. LifeCell Biologics focuses to cater a wide range of placental tissue derived therapeutic products to provide solutions to enhance patient life expectancy and reduce global disease burden.

We are dedicated towards pushing the boundaries of science to develop and deliver life-changing health care products to make a difference in the life of patients while reducing the average cost of healthcare. In addition to our current product AmchoPlast, LifeCell Biologics is expecting to launch a series of products derived from placental tissues which are presently under rigorous research and developmental pipeline.

Our research design and practices are fabricated to exceed the industry standard globally. A perfect blend of state-of-art research, extremely talented team and hi-tech manufacturing infrastructure have enabled us to stand alone as a well-recognized leading biotech company.

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LifeCell - India's First and Largest Stem Cell Bank

Buy PRP Kits & Stem Cell Therapy Supplies for Regenerative …

By Stem Cell Doctors

Details:

Apex Biologix understands the challenges of increased medical supply costs and a patients desire to receive quality care at an affordable cost. XCELL PRP was designed to deliver on those needs. No longer do you have to choose between a low-cost PRP system with low concentration numbers and an overpriced priced system.

Ease of Use

Using our patented processing accessories (lead screw, benchtop processing station) you can easily capture the buffy coat through a convenient push method. The buffy coat layer and easier-to-read markings on the kit allow a user to accurately obtain reproducible results consistently. Overall processing time is quicker, has fewer steps than most systems on the market, and fits into many centrifuge systems.

Kit Contents

2 - SYRINGE 60CC (LUER LOCK) 1 - NEEDLE 18G X 1" 1 - SYRINGE 12CC (LUER LOCK) 1 - Luer, 45 Degree Bent, Dispensing Tip 1 - APEX P60A Concentrating Device 1 - APEX P60A Cap 4 - ALCOHOL PREP PAD - NON-STERILE SOLUTION 5 - GAUZE SPONGE 4 X 4-8 PLY 2 - ADHESIVE BANDAGE 1 - LATEX FREE TOURNIQUET 1 - ABSORBENT TOWEL 2 - GLASSINE BAG 1 - HOSPITAL WRAP 1 - HEADER BAG 1 - MEDIUM POWDER-FREE SYNTHETIC GLOVE LATEX FREE 1 - YELLOW FACE MASK EARLOOPS 3 - UNIVERSAL MALE/FEMALE NON-VENTED CAP 1 - MALE LUER CAP 4 - WHITE BLANK LABEL

Available Sizes and Product Number:

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Buy PRP Kits & Stem Cell Therapy Supplies for Regenerative ...

Stem Cell Therapy Atlanta Home – Southern Stem Cell Institute

By Stem Cell Medical Center

Dr. Ambrozic has been a physician for over 20 years, and during that time, he earned his medical degree from the University of Alberta and completed a residency in health prevention and family medicine at the University of British Columbia (both Universities Medical programs are among the best in the world). Dr. Ambrozic was the assistant team physician of the University of British Columbia Thunderbirds Football Team during that time. After moving to the United States, he was also the assistant emergency director for a couple of emergency rooms in South Georgia. Dr. Ambrozics journey in regenerative medicine began early while he was in medical school. He conducted research into wound healing and burns involving growth factors. He also completed a fellowship at the University of South Florida in anti-aging and esthetics, where he furthered his learning and training in regenerative medicine. Committed to excellence and lifelong learning, he is also a member of the Harvard Medical School Postgraduate Association.

He has worked with numerous world leaders in medical care and treated many athletes and celebrities. He founded Southern Stem Cell Institute with the mission to be Committed to Research and Using State of the Art Stem Cell and Regenerative Therapies in an Ethical and Safe Manner.

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Stem Cell Therapy Atlanta Home - Southern Stem Cell Institute

Tracing the origin of adult intestinal stem cells | Nature

By Adult Stem Cells

Clevers, H. The intestinal crypt, a prototype stem cell compartment. Cell 154, 274284 (2013).

Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 10031007 (2007).

Shyer, A. E., Huycke, T. R., Lee, C., Mahadevan, L. & Tabin, C. J. Bending gradients: how the intestinal stem cell gets its home. Cell 161, 569580 (2015).

Nigmatullina, L. et al. Id2 controls specification of Lgr5+ intestinal stem cell progenitors during gut development. EMBO J. 36, 869885 (2017).

Tetteh, P. W. et al. Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell 18, 203213 (2016).

van Es, J. H. et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nat. Cell Biol. 14, 10991104 (2012).

Buczacki, S. J. et al. Intestinal label-retaining cells are secretory precursors expressing Lgr5. Nature 495, 6569 (2013).

Yui, S. et al. YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration. Cell Stem Cell 22, 3549 (2018).

Nusse, Y. M. et al. Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature 559, 109113 (2018).

Guiu, J. & Jensen, K. B. From definitive endoderm to gut-a process of growth and maturation. Stem Cells Dev. 24, 19721983 (2015).

Sumigray, K. D., Terwilliger, M. & Lechler, T. Morphogenesis and compartmentalization of the intestinal crypt. Dev. Cell 45, 183197 (2018).

Mustata, R. C. et al. Identification of Lgr5-independent spheroid-generating progenitors of the mouse fetal intestinal epithelium. Cell Reports 5, 421432 (2013).

Moor, A. E. et al. Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis. Cell 175, 11561167 (2018).

Merlos-Suarez, A. et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8, 511524 (2011).

Shyer, A. E. et al. Villification: how the gut gets its villi. Science 342, 212218 (2013).

Walton, K. D. et al. Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi. Proc. Natl Acad. Sci. USA 109, 1581715822 (2012).

Itzkovitz, S., Blat, I. C., Jacks, T., Clevers, H. & van Oudenaarden, A. Optimality in the development of intestinal crypts. Cell 148, 608619 (2012).

Sato, T. et al. Single Lgr5 stem cells build cryptvillus structures in vitro without a mesenchymal niche. Nature 459, 262265 (2009).

Fordham, R. P. et al. Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell 13, 734744 (2013).

Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618623 (2012).

Ritsma, L. et al. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. Nature 507, 362365 (2014).

Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255259 (2011).

Chan, C. J., Heisenberg, C. P. & Hiiragi, T. Coordination of morphogenesis and cell-fate specification in development. Curr. Biol. 27, R1024R1035 (2017).

Hannan, N. R. et al. Generation of multipotent foregut stem cells from human pluripotent stem cells. Stem Cell Reports 1, 293306 (2013).

Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105109 (2011).

Watson, C. L. et al. An in vivo model of human small intestine using pluripotent stem cells. Nat. Med. 20, 13101314 (2014).

Sun, X. et al. Directed differentiation of human embryonic stem cells into thymic epithelial progenitor-like cells reconstitutes the thymic microenvironment in vivo. Cell Stem Cell 13, 230236 (2013).

McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400404 (2014).

Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443452 (2008).

Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593605 (2007).

Means, A. L., Xu, Y., Zhao, A., Ray, K. C. & Gu, G. A CK19CreERT knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 46, 318323 (2008).

Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134144 (2010).

el Marjou, F. et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186193 (2004).

Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133140 (2010).

Walton, K. D. & Kolterud, A. Mouse fetal whole intestine culture system for ex vivo manipulation of signaling pathways and three-dimensional live imaging of villus development. J. Vis. Exp. 91, e51817 (2014).

Zheng, G. X. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).

Fan, J. et al. Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Nat. Methods 13, 241244 (2016).

Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411420 (2018).

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Tracing the origin of adult intestinal stem cells | Nature

4 Barriers To Cell And Gene Therapy Development For Rare …

By Gene Therapy Clinics

By Ben Solaski and Perry Yin, Ph.D., PA Consulting

Rare diseases, as defined by the Orphan Drug Act, are diseases that affect less than 200,000 people. Given that approximately 80 percent of the 7,000 known rare diseases are caused by a single-gene defect,1 there has been increased research in the development of cell and gene therapies to treat rare diseases.

However, a number of challenges hinder these efforts, including pricing and reimbursement, the high cost of bringing these drugs to market, unique manufacturing and supply chain challenges, and our current limited understanding of disease pathology and progression. While these challenges may seem common across other drug markets, in the case of rare diseases, these challenges are exacerbated by limited patient populations. In this article, we look at the four challenges in greater depth and explore potential responses to help pharma companies be successful in bringing these products to market.

1. Making Commercialization Viable By Tackling High Costs Together

Given the small patient population, and the high price of drugs aimed at rare diseases, how can we ensure the long-term commercial viability of these drugs? This challenge can be explored from two points of view - how health authorities can promote scientific advancements while also protecting investments in rare disease development and how pharma can collaborate with payers to find better pricing solutions to reduce hurdles for patients to receive treatment.

Over the years, the FDA has taken concrete steps to incentivize the industry to develop drugs for rare diseases. In 2017, the FDA sought to eliminate the backlog for orphan drug requests by responding to future requests within 90 days.2 More recently, the FDA released a Draft Guidance on Human Gene Therapy for Rare Diseases, which pledges that the FDA will be involved with drug companies earlier in the development process. This will not only help streamline development by helping limit the number of preclinical or other preparatory studies but will also lower development costs and increase speed to market.3 But is this enough? There is ongoing debate in the pharma industry that the FDA needs to go even further. For example, while the agency already grants a longer exclusivity period for orphan drugs, this seven-year period is usually outlasted by the 20-year protection offered by patents.4 To sweeten the deal, the FDA may need to consider offering increased protection by expanding this exclusivity period. This would make these drugs more commercially viable, better ensuring capture of initial and ongoing investment in small markets or providing an option for improved pricing scenarios.

On the payer front, as the healthcare industry shifts toward value-based healthcare, orphan drugs and cell and gene therapies that have been prohibitively expensive will be prime candidates for emerging pricing models derived from measuring health outcomes against the cost of treatment. One great example is Novartis CAR-T treatment, Kymriah. For this treatment, Novartis only receives payment if the patient shows significant improvement within a month; otherwise, Novartis bears the cost. The use of value-based pricing models for cell and gene therapies would ease the amount of risk that payers take on when reimbursing these treatments, while also increasing the likelihood that patients will have access to these drugs.

With higher rates of approvals, longer periods of exclusivity, and greater utilization of value-based pricing, cell and gene therapies for rare diseases will have a greater chance of both reaching patients and being commercially successful.

2. Improving Clinical Development: A New Age In Clinical Trial Design And Recruitment

Companies developing cell and gene therapies for rare diseases are confronted with many of the same challenges faced by more traditional drugs; however, these challenges are amplified. These challenges include small patient populations, high mortality rates, and lack of disease state understanding, making it difficult to set clinical endpoints.

Seeking to address this, the FDAs Draft Guidance on Human Gene Therapy for Rare Diseases focuses on new clinical trial designs. What will these trials of the future look like? Gone are the days of three-phase randomized, controlled clinical trials. New age trials for rare diseases will be shorter, combining phases to show both safety and efficacy. Later stage trials will be replaced with rollover studies to see longer-term effects of treatment. Control groups will be replaced with natural history studies to illustrate what happens when patient groups go untreated. Natural history studies will also help to identify surrogate endpoints that can serve as early indicators of future outcomes to help expedite trials.

While these trial designs will help improve the process, there is still the inherent issue of recruiting from such small and geographically diverse patient populations. To ease this, there will be increasing demand for accurate patient registries that include relevant information about potential biomarkers for treatment. GSKs partnership with 23andMe is a good example of how this would work. Genetic data is captured through commercial genetic testing, then used to drive novel drug development and identify patients with specific rare diseases for trial recruitment. Pharma and CROs will also leverage increased use of digital technology to execute remote or highly fragmented multisite trials, making trial participation easier for patients.

Streamlining the clinical trial pathways for gene therapy and rare diseases, as well as reducing the burden on the patient, allows pharma companies to accelerate products to market.

3. Overcoming The Challenges Of Manufacturing And Supply Chain By Partnering With Contract Manufacturer Organizations

There are two major manufacturing challenges. The first is addressing the need for new infrastructure such as advanced supply chains, since the effective handling of these treatments will often require a high degree of customization for the patient (e.g., CAR T cell therapies). The other challenge lies with rare disease and cell and gene therapy products, whose manufacturing requires specialized skills where there is little room for error. As such, organizations will need to decide if they will build the capability or leverage contract organizations.

To address these challenges, in the short term, it is essential that companies have robust chain of custody protocols and supporting technologies to track and monitor these drug products from factory to patient. This ensures the correct patient is getting the therapy that was specifically designed for them, and that the conditions in transit do not damage the drug product. Longer term, the rise of a larger number of small manufacturing sites spread across the country is expected. Smaller manufacturing sites distributed in key geographic regions reduce shipping time, thus reducing the possibility for delays. Taking this one step further, imagine a world where manufacturing sites do not exist, and hospitals or clinics will have the capability and infrastructure to perform specialized manufacturing on-site.

How can pharma get to a commercial scale to support successful complex manufacturing requiring specialized skills? One solution is to outsource manufacturing to contract manufacturing organizations (CMOs) that specialize in gene therapies and rare diseases, similar to the way that clinical research has increasingly relied on contract research organizations (CROs). CMOs manufacture the product as a service and use their expertise to produce high-quality product at a reduced cost.

By using specialists to support the manufacturing process and technology to monitor and localize the supply chain, companies can reduce the risks involved in getting high-quality products to patients.

4. Increasing Our Understanding Of Disease States: The Rise Of Natural History Studies And Companion Diagnostics

Currently, there is a lack of understanding of rare diseases, especially around diseases variations and subtypes. This creates the challenge of how to better identify these variations to develop treatments that are then targeted at a specific disease subtype.

Pharma companies will need to spend more time and effort understanding disease states. For rare diseases, natural history studies are critical to provide insight that could help to drive early development, and even serve as a control group in single-arm studies if randomized, concurrent controlled trials are not feasible.5 Natural history studies may also help identify biomarkers that will help tailor these cell and gene therapies to be more personalized to specific subgroups of patients, allowing companies to be more focused in the development process.

Furthermore, to get the best results from treatment, the patient population that would benefit most from treatment needs to be identified. Thus, the industry will likely see an increase in products entering the market that include a companion diagnostic. Both the FDA and payers have an incentive to require drug manufacturers to develop these diagnostics in parallel with drug projects to ensure the best patient outcomes possible. Advancements in next-generation sequencing techniques will make identifying these subgroups easier and more accurate, potentially leading to a one size fits all genetic test that could be applied to all rare disease products.

Genetic tests, combined with an increase in understanding of natural history and disease biomarkers, will ensure the correct patients are receiving the therapies being developed.

Conclusion

Cell and gene therapies for the rare disease space are still emerging and will continue to face new challenges around development, the evolving regulation landscape, pricing and reimbursement, and manufacturing. Despite these challenges, the first products have already reached the market. New approaches and solutions, such as some of those outlined in this article, will go a long way to meeting these challenges and reducing the barriers to entry, allowing pharma to bring these products to market more quickly and affordably.

References:

About The Authors:

Ben Solaski is a life sciences expert at PA Consulting. With his training as a biomedical engineer, he has extensive experience with the development of gene editing technologies and an understanding of their potential to disrupt the industry. Contact him on LinkedIn at https://www.linkedin.com/in/benjaminsolaski/.

Perry Yin, Ph.D., is a life sciences expert at PA Consulting, where he leads the Cell and Gene Therapy group. He has experience developing technologies like CRISPR and stem cell-based therapies from concept to animal testing for both cancer and regenerative medicine applications. Contact him on LinkedIn at https://www.linkedin.com/in/yinperry/.

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4 Barriers To Cell And Gene Therapy Development For Rare ...

Dr. Bermans’s Stem Cell Therapy – Mark Berman MD

By Stem Cell Medical Center

Dr. Berman talks about his research in fat stem cells.

Most people (doctors included) believe that stem cell therapy is still several years away from being available to the public. However, since 2010, in association with my partner, urologist Elliot Lander, MD, FACS, we have been conducting stem cell deployment as part of an ongoing investigative project collecting data on thousands of treated patients. After several successful outcomes in the orthopedic arena that I obtained in collaboration with orthopedic surgeon, Dr. Tom Grogan, Elliot and I formed the California Stem Cell Treatment Center followed a year later by the Cell Surgical Network the worlds largest network of stem cell physicians utilizing technology we developed with renown Korean plastic surgeon, Dr. Lee Hee Young. We currently teach doctors from the USA and worldwide our techniques using the CSN Time Machine to effectively harvest and process fat into stromal vascular fraction (SVF) rich in stem cells. Starting with a 10 minute mini-liposuction painlessly done under local anesthesia, this 1 hour process has yielded results that have been successfully recapitulated all over the world. Currently, there are about 100 CSN centers in the US and many more throughout the world, including dozens in China in association with our partners, RE Stem Biotech.

We are now in a new era of medicine. Our bodies are made up of dozens of trillions of cells. Up until now, medicine was predominantly aimed at keeping our cells healthy and alive through diet, exercise, medications to eradicate disease, or supplements to help our cells stay healthy, but now, going forward, we have the opportunity to replace injured or dying cells with our own DNA coded stem cells. These cells can not cause an allergic response or be rejected. While many people consider this experimental, we really consider it investigational but not really experimental. This may be a NEW era in medicine, but it really reflects perhaps the OLDEST form of intervention. Before we had any kind of medical intervention we had to rely on our bodys natural cell defense to keep us healthy. We now have the ability to unlock and harvest huge quantities of these repair cells for immediate use and, further, we can send samples to our lab where they can be cryopreserved and expanded as millions of stem cells for later use. Indeed, we have coined the term CRT Cell Renewal Therapy to describe how we foresee the future of medicine whereby your natural spare parts in the form of your own DNA cultivated stem cells will be made available to keep your body healthy and extend longevity for years beyond anything ever imaginable.

Stem cells are basically unspecialized cells that can replicate and differentiate (i.e. turn into other specialized cells). They tend to have three basic properties: 1) anti-inflammatory; 2) immune-modulatory and 3) reparative or regenerative. Most people think an embryo is the most common source for stem cells. While most stem cell studies started by using embryos, there are a number of issues and problems associated with their use. Not only are there ethical concerns, embryonic stem cells can sometimes form tumors (i.e. teratomas).

There are also a lot of stem cells naturally found in our body. Most people are aware of bone marrow derived stem cells. In recent years, bone marrow has been a source for stem cells particularly for orthopedic conditions. However, stem cell yields in bone marrow tend to be between 50,000 and 200,000 with some of the newer technology. Adipose (fat) tissue also houses vast quantities of stem cells. In fact, just 30 ccs (2 tablespoons) of fat can yield between 10 and 30 million stem cells.

Our fat derived stem cells have a tremendous capacity to turn into a large variety of tissues. Originally, because of their mesenchymal origin we thought they could only turn into fat, cartilage, bone, muscle, connective tissue, blood vessels and nerve tissue, but now we have studies showing theyve turned into practically every kind of cell in the body. While the bone marrow proponents will sing the virtues of bone marrow stem cells for cartilage repair, it turns out that fat derived cells are an even greater source for cartilage repair and production. Compared to a bone marrow harvest, its so simple to harvest a little fat and the yields are generally very high making fat an ideal source for stem cells.

When we started our studies in 2010 the critics suggested it might not be safe. Our initial study made SAFETY the primary objective and the clinical outcomes a secondary objective. Our safety study of over 1500 patients has shown that there are no significant adverse events related to the deployment of SVF. Indeed, the only real issues have been some mild discomfort around the liposuction site something we naturally expect. Weve submitted this paper for publication.

While there are a growing number of doctors claiming to provide stem cell treatments, we believe the most ethical approach is to do it under the umbrella of IRB approved research protocols. An IRB is an Institutional Review Board or an organization of members responsible for approving and overseeing research on humans. IRBs are approved under the auspices of the U.S. Department of Human Research Protection. As such, our patients understand the investigational nature of our activities, are provided appropriate informed consents, and are followed continuously on an online database to chart their progress or any issues of concern. This will allow us to not only accumulate safety data but demonstrate effectiveness of treatments and help us to improve treatment programs going forward.

We already have a number of very innovative treatments in progress. For example, one of our approved studies involves deployment of cells via an Ommaya reservoir. This is a device that connects a port under the scalp via a tube directly into the ventricle of the brain where cells can be added to the cerebral spinal fluid. This concept evolved by working with renown Brain Surgeon, Christopher Duma, MD, FACS. It was preceded by safety studies on laboratory rats and 30 patients later is showing some significant progress.

As you can imagine, with new technologies, patients often come to you when theyve exhausted most other traditional treatments. Weve now had a lot of experience to understand how well cell therapy can work even though were continuing to gather data and look for ways of optimizing treatments. So, for example, most patients with arthritic knees will consider stem cell deployment after theyve tried pain medication, steroids, hyaluronan injections and even arthroscopy. None of these are actually treatments that repair the problem but rather mask the pain or temporize the situation. If theres cartilage in the knee then it can potentially signal your stem cells to repair the joint. We now understand that acute injuries probably respond better than chronic ones because there are more messages (cytokines) directing and instructing the stem cells into action and repair. Still, until we have enough data and publish enough articles to support these positions our concepts remain conjecture awaiting to be proven.

Patients are also concerned about whether these procedures are FDA approved. Technically, the FDA only approves drugs and devices. Were actually performing a surgical procedure and the FDA does not approve surgery. However, we are working with the FDA to have our system evaluated for potential FDA approval. Our initial FDA studies will be aimed at knee arthritis with the goal to show autologous SVF is more effective than a placebo. This will be done with a double blind controlled study. I doubt we will do FDA studies for every potential condition rather, doctors will ultimately gather data and/or do their own research and accumulate results to support the positive use of SVF for a large host of inflammatory and degenerative conditions.

Since starting our investigative network in 2012, weve not only gone to the animal lab for the Ommaya reservoir program, weve expanded our research into areas of cancer, paralysis, and most recently, concussion. My son, Sean, in fact, has been doing some terrific animal research in the area of concussion where hes been able to first, induce reproducible concussions in trained animals and show that they generally take two weeks to get better and re-learn their memory and motor skills; and second, by giving SVF via a tail vein injection after concussion, the rats get better so quickly that they regain their memory and motor skills right away. The implications for athletes, football especially, and the military are extraordinary.

There is a lot more information about our program that can be found at our website stemcellrevolution.com. Still, while this currently remains an area of investigation, it also represents one of the most exciting transitions in the field of medicine with tremendous potential now and in the future.

Read the latest news articles about Dr. Berman's Stem Cell work: Latest Stem Cell News about Dr. Berman

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Dr. Bermans's Stem Cell Therapy - Mark Berman MD

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