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Tumor Associated Macrophages: The Double-Edged Sword Resolved?

Writer/Curator: Stephen J. Williams, Ph.D.

Cell-based immunity is vital for our defense against pathologic insult but recent evidence has shown the role of cell-based immunity, especially macrophages to play an important role in both the development and hindrance of tumor growth, including role in ovarian, hematologic cancers, melanoma, and breast cancer.  In the past half century, new immunological concepts of cancer initiation and progression have emerged, including the importance of the harnessing the immune system as a potential anti-cancer strategy. However, as our knowledge of the immune system and tumor biology has grown, the field has realized an immunological conundrum: how can an immune system act to both prevent tumor growth and promote the tumor’s growth?

As discussed in the lower section of this post, authors of a paper in the journal Science show how different populations of tumor-associated macrophages (TAMs) may exert both positive and negative effects on tumor cells, producing a sort of ying-yang war between the tumor and the immune system.

The Immune System: Brief Overview and Role in Cancer

celllineageimmunesystem

 

 

 

 

Figure. Cell lineage of the immune system. A description of the different cell types can be found here.

 

 

 

 

 

 

Histologic evaluation of multiple tumor types, especially solid tumors, reveal the infiltration of diverse immunological cell types, including myeloid and lymphoid cell lineages, such as macrophages and NK, T cell and B cells respectively.

The immunological conundrum

immuncecancerconundrum

 

Figure. Potential inflammatory signaling pathways in breast cancer stem cells.
Breast cancer stem cells may be regulated by chemokine- and/or cytokine-mediated inflammatory signaling in an autocrine or paracrine manner. (from University of Tokyo at http://www.ims.u-tokyo.ac.jp/system-seimei/en/research2_e.htm)

 

Role of Tumor Associated Macrophages

There are conflicting reports as to the functional consequence of these infiltrating tumor-associated macrophages (TAMs). TAMs have been shown to secrete mediators such as interleukins and cytokines in a paracrine manner such as CCL2, IL10 and TGFβ. In certain instances these cytokines and mediators actually promote the growth of the surrounding tumors.

J Leukoc Biol 2009 Nov 86(5) 1065-73, Figure 1

 

 

 

Figure.  TAMs can be divided into subpopulations with distinctive functions and secretogogues.

 

For Further Reference

Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/23089461 anti-inflamm IL10 and TGFB

Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner

TAMscytokines

 

Figure 2: TAM functions in tumor progression. Tumor cells and stromal cells, which produce a series of chemokines and growth factors, induce monocytes to differentiate into macrophages. In the tumor, most macrophages are M2-like, and they express some cytokines, chemokines, and proteases, which promote tumor angiogenesis, metastasis, and immunosuppression. From Macrophages in Tumor Microenvironments and the Progression of Tumors

 

 

 

 

 

 

ICB-14-NC-BRONTE-V2

Macrophages integrate metabolic and environmental signals to promote tumor growth. Area within dotted rectangle indicates proposed mechanisms of action. ARG, arginase; HIF, hypoxia-inducible factor; MCT, monocarboxylate transporter; NADH, nicotine adenine dinucleotide, reduced; PKM2, M2 isoform of pyruvate kinase; VEGF, vascular endothelial growth factor from Tumor cells hijack macrophages via lactic acid adapted from Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM, Jairam V et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature (e-pub ahead of print 13 July 2014; doi:10.1038/nature13490). | Article |

Depletion of M2-Like Tumor-Associated Macrophages Delays Cutaneous T-Cell Lymphoma Development In Vivo

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration

Tumor-Associated Macrophages Regulate Murine Breast Cancer Stem Cells Through a Novel Paracrine EGFR/Stat3/Sox-2 Signaling Pathway

Science Paper: Different Populations of TAMS Have Different Tumor Effects

The cellular and molecular origin of tumor-associated macrophages Eric G. Pamer1 Ruth A. Franklin1,2, Will Liao3, Abira Sarkar1, Myoungjoo V. Kim1,2, Michael R. Bivona1, Kang Liu4, Ming O. Li1, Science 23 May 2014: Vol. 344 no. 6186 pp. 921-925

A recent Science paper from Cornel has investigated the origin, function, and characterization of TAMs on breast cancer growth. In summary, their efforts and research suggest different populations of TAMs with varied tumorigenic effects, a finding which may help explain the immunologic conundrum with respect to solid tumors.

The authors characterized the infiltrating immune cell types in a MMTV-PyMt model of breast cancer.

 

The MMTV-PyMt mouse breast cancer model:

is a transgenic model where mammary gland expression of the polyoma middle T antigen (PyMT) is driven by the Mouse Mammary Tumor Virus promoter (MMTV).

Microbiol. Mol. Biol. Rev. 2009 Sep 73(3) 542-63, FIG. 5

 

 

 

 

 

 

 

 

 

For a review of mouse models of breast cancer please see

Mouse models of breast cancer metastasis. Anna Fantozzi1 and Gerhard Christofori. Breast Cancer Res. 2006; 8(4): 212.

 

Results

1.     Macrophages constitute the predominate myeloid cell population in MMTV-PyMT mammary tumors

Tumor infiltrating immune cells included

  • Myeloid cells comprised 50% of CD45+ infiltrating leukocytes.
  • The CD45 antigen, also known as Protein tyrosine phosphatase, receptor type, C (PTPRC) is an enzyme that, in humans, is encoded by the PTPRC gene, and acts as a regulator of B and T-lymphocytes.
  • Authors noted three types of cells classified as Type I, II, and III based on
  1. Cell morphology
  2. Major histocompatibility complex
  • Infiltrating monocytes and neutrophils
  • Cells with dendritic and macrophage markers

 

2. TAMS differentiate from CCR2+ inflammatory monocytes

  • To determine whether Ly6C+CCR2+ inflammatory monocytes contributed to TAMs and MTMs, authors crossed PyMT mice to Ccr2−/− mice and found MTMs (mammary tumor macrophages) were significantly reduced in Ccr2−/− PyMT mice, implying that MTMs are constitutively repopulated by inflammatory monocytes
  • To determine whether inflammatory monocytes were required for TAM maintenance, we generated CCR2DTR PyMT mice expressing diphtheria toxin receptor (DTR) under control of the Ccr2 locus DT treatment resulted in 96% depletion of tumor-associated monocytes compared to 80% depletion in Ccr2−/− mice
  • To investigate whether monocytes could differentiate into TAMs in vivo, we transferred CCR2+ bone marrow cells isolated from CCR2GFP reporter mice into congenically marked CCR2DTR PyMT mice depleted of endogenous monocytes, we observed transferred cells in developing tumors demonstrate that tumor growth induces the differentiation of CCR2+ monocytes into TAMs.

 

3.     TAMs are phenotypically distinct from AAMs (M2 or alternatively activated macrophages)

  • Gene-expression profiling revealed the integrin CD11b (Itgam) was expressed at lower levels in TAMs than in MTMs while several other integrins and the integrin receptor Vcam1 were up-regulated in TAMs
  • AM population did not express AAM markers such as Ym1, Fizz1, and Mrc1; instead, MTMs more closely resembled AAMs. The authors detected Vcam1 up-regulation on TAMs as a late differentiation event

 

4.    RBPJ-dependent TAMs modulate the adaptive immune response

  • In DCs, canonical Notch signaling mediated by the key transcriptional regulator RBPJ controls lineage commitment and terminal differentiation. To explore whether Notch signaling played a role in TAM differentiation, authors used CD11ccre mice that efficiently deleted floxed DNA sequences to a greater extent in TAMs than MTMs, but not in monocytes or neutrophils (fig. S14). CD11ccreRbpjfl/fl PyMT mice exhibited a selective loss of MHCIIhiCD11blo TAMs ( 4A). However, a MHCIIhiCD11bhi population still remained
  • Transcriptional profiling comparing this population to WT TAMs confirmed a loss of the Notch-dependent program in RBPJ-deficient cells revealing that in the absence of RBPJ, inflammatory monocytes are unable to terminally differentiate into TAMs.

 

Other posts on this site on Immunology and Cancer include

The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

Innovations in Tumor Immunology

T cell-mediated immune responses & signaling pathways activated by TLRs

Vaccines, Small Peptides, aptamers and Immunotherapy [9]

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Immunotherapy in Cancer: A Series of Twelve Articles in the Frontier of Oncology by Larry H Bernstein, MD, FCAP

 

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Detecting and Treating Silent Heart Disease: NewYork-Presbyterian Hospital and Weill Cornell Medical College Launch New Institute

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/15/2018

The Dalio Institute

The Dalio Institute for Cardiovascular Imaging at NewYork-Presbyterian Hospital combines research, clinical care and education to uncover new answers about preventing heart disease. A joint NewYork-Presbyterian Hospital and Weill Cornell Medicine venture, the institute employs a multidisciplinary, multimodality approach to the detection and treatment of heart disease. Directed by Dr. James K. Min, the institute’s mission is to innovate, integrate and educate, goals that will be achieved through cutting-edge research, transformations of current clinical paradigms and dissemination of knowledge.

Rooted in the central role of imaging techniques to better diagnose cardiovascular disease, the institute not only uses state-of-the-art tools such as MRI, CT and PET scanners, but also focuses on the development of novel next-generation technologies and diagnostic tests. Applying a team-based approach that draws on the expertise of physicians and scientists in radiology, cardiology, genetics, proteomics, and computational biology, the institute’s primary research initiative is to identify the specific coronary artery lesion that is responsible for heart attacks or sudden cardiac deaths.

The Dalio Institute uses imaging technologies in conjunction with other cutting-edge diagnostic tests, including blood markers of inflammation, protein expression and metabolism. The clinical program serves patients in the outpatient and inpatient setting, as well as in the emergency department. Three specific initiatives within the clinical program emphasize early identification of heart disease in women, ethnic minorities and young patients with a family history of premature heart disease.

https://hearthealth.weillcornell.org/about-us/dalio-institute

Based on your medical history, we can use calculators to estimate your risk of having a cardiovascular event over time. Risk calculators use various factors including age, sex, and race, in addition to “traditional” cardiac risk factors such as smoking, diabetes, high cholesterol and high blood pressure. Our practice uses several common risk calculators. It is important to emphasize that risk calculators may be imperfect, especially in patients with unique risk factors. These might include a family history of early heart disease or a chronic inflammatory disorder. Therefore, it may be beneficial to consider a full cardiovascular assessment to explore your personal risk and strategies to reduce it.

Risk calculators may be of interest to you, but we caution that the results should be interpreted and reviewed by a trained clinical provider.

https://hearthealth.weillcornell.org/risk-assessments

Diagnostic Tests

 

Your cardiovascular risk assessment at HeartHealth always begins with a detailed medical history and physical exam.  The physical exam is often not able to fully diagnose problems, nor is it ever able to diagnose coronary artery disease or calcification.  We therefore offer the most up-to-date noninvasive imaging studies to visualize the heart muscle, valves, blood flow and coronary arteries.  We have state-of-the-art equipment and world-renowned experts to interpret these studies.

All of the following will be offered at HeartHealth (Click on the test name to view more information):

  • Cardiac Computed Tomography Angiography (CTA)
  • Cardiac Magnetic Resonance Imaging (MRI)
  • Cardiac PET/CT
  • Echocardiogram/Doppler Transthoracic
  • Exercise Electrocardiogram or ETT (Exercise Treadmill Test)
  • Exercise Stress Echocardiogram & Dobutamine Stress Echocardiogram
  • Myocardial Perfusion Scan (aka Nuclear Stress Test)

HeartHealth

A Program of the Dalio Institute of Cardiovascular Imaging
at the NewYork-Presbyterian Hospital
1305 York Avenue, 8th Floor
New York, NY 10021 Map ThisP: (646) 962-4278 (HART)F: (646) 962-0188

 

 

November 12, 2013
Funded by a $20 million gift from the Dalio Foundation, the institute will combine research, clinical care, and education to uncover new answers about preventing heart disease
NEW YORK – To help reduce the burden of cardiovascular disease, the nation’s leading killer, NewYork-Presbyterian Hospital and Weill Cornell Medical College have created the Dalio Institute of Cardiovascular Imaging. Raymond T. Dalio, a life trustee of NewYork-Presbyterian Hospital, has made a gift of $20 million through his Dalio Foundation in support of the institute.

The Dalio Institute of Cardiovascular Imaging will employ a multidisciplinary, multimodality approach to the detection and treatment of heart disease, with a focus on finding new answers about prevention of heart disease in at-risk individuals and ultimately save lives. Its mission is to innovate, integrate, and educate, goals that will be achieved through cutting-edge research, transformations of current clinical paradigms, and dissemination of knowledge. Dr. James K. Min, an expert in cardiovascular imaging and a physician-scientist who has led several large-scale multicenter clinical trials, has been appointed director of the Dalio Institute of Cardiovascular Imaging. Dr. Min is an attending physician at NewYork-Presbyterian Hospital and a full-time faculty member in the Department of Radiology at Weill Cornell Medical College. He joins NewYork-Presbyterian/Weill Cornell from the Cedars-Sinai Medical Center, where he was director of cardiac imaging research and co-director of cardiac imaging. Rooted in the central role of imaging techniques to better diagnose cardiovascular disease, the institute will not only use state-of-the-art tools such as MRI, CT, and PET scanners, but will also focus on the development of novel next-generation technologies and diagnostic tests. Applying a team-based approach that draws on the expertise of physicians and scientists in radiology, cardiology, genetics, proteomics, and computational biology, the institute’s primary research initiative is to identify the “vulnerable plaque,” or the specific coronary artery lesion that is responsible for a future heart attack or sudden cardiac death.“The vulnerable plaque is the holy grail in the diagnostic work-up of individuals with suspected coronary artery disease, and its elusive nature has precluded the timely treatment of millions of high-risk individuals,” says Dr. Min. “We will apply an array of innovative hardware and software imaging technologies to improve identification of the vulnerable plaque, and then seek to apply these findings in large-scale multicenter clinical trials and registries to encourage full integration of our research findings into clinical practice.”
To develop the world-class clinical program to diagnose early cardiovascular disease, the Dalio Institute of Cardiovascular Imaging will use state-of-the-art imaging technologies in conjunction with other cutting-edge diagnostic tests, including blood markers of inflammation, protein expression, and metabolism. The clinical program will serve patients in the outpatient and inpatient setting, as well as in the emergency department. Three specific initiatives within the clinical program will emphasize
  • early identification of heart disease in women,
  • ethnic minorities, and
  • young patients with a family history of premature heart disease. 

The institute’s educational mission will focus on disseminating knowledge of the latest advances in cardiovascular imaging through the education of physicians, physician trainees, and allied health professionals through formal didactic curricula and symposia.

“More than half of people who die from sudden heart attacks never knew they were at risk because their underlying heart conditions had never been diagnosed,” says Dr. Min. “Many heart attacks can be prevented if people know of the extent and severity of their asymptomatic heart disease and are properly treated. By bringing together a multidisciplinary group of experts, the Dalio Institute of Cardiovascular Imaging will not just offer the latest imaging techniques for early detection, but will also develop disruptive technologies to fight the battle against heart disease. Ultimately, these pioneering methods aim to challenge current clinical paradigms in order to reduce the morbidity and mortality associated with cardiovascular disease.” 

“Establishing the Dalio Institute of Cardiovascular Imaging is an incredibly significant milestone in our fight against heart disease,” says Dr. Steven J. Corwin, CEO of NewYork-Presbyterian Hospital and a cardiologist by training. “While modern medicine offers highly sophisticated tools for treating heart disease, we still have a long way to go in terms of identifying high-risk individuals with early-stage disease so that we can prevent catastrophic outcomes and save lives. Dr. Min’s unique background, expertise, and clinical research experience make him ideally suited to lead the institute and its groundbreaking initiatives. We are thrilled that Dr. Min has joined us, and we are extraordinarily grateful to Ray Dalio for his vision and generous support.”

“The interdisciplinary nature of the new Dalio Institute of Cardiovascular Imaging exemplifies the best in translational research – investigations that can make lifesaving impact on our patients,” says Dr. Laurie H. Glimcher, the Stephen and Suzanne Weiss Dean of Weill Cornell Medical College. “Dr. Min has a proven track record of effectively testing novel theories, and we enthusiastically support what we know will be innovative research at the institute.”

NewYork-Presbyterian/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital NewYork-Presbyterian and Weill Cornell Medical College, the medical school of Cornell University. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, education, research and community service. Weill Cornell physician-scientists have been responsible for many medical advances – including the development of the Pap test for cervical cancer; the synthesis of penicillin; the first successful embryo-biopsy pregnancy and birth in the U.S.; the first clinical trial for gene therapy for Parkinson’s disease; the first indication of bone marrow’s critical role in tumor growth; and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. NewYork-Presbyterian Hospital also comprises NewYork-Presbyterian/Columbia University Medical Center, NewYork-Presbyterian/Morgan Stanley Children’s Hospital, NewYork-Presbyterian/Westchester Division, NewYork-Presbyterian/The Allen Hospital, and NewYork-Presbyterian/Lower Manhattan Hospital. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best academic medical institutions in the nation, according to U.S.News & World Report. Weill Cornell Medical College is the first U.S. medical college to offer a medical degree overseas and maintains a strong global presence in Austria, Brazil, Haiti, Tanzania, Turkey and Qatar. For more information, visit http://www.nyp.org and weill.cornell.edu.
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Reporter: Aviva Lev-Ari, PhD, RN

Public release date: 18-Oct-2012
Contact: Lauren Woods
law2014@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College

 

New study shows reprogrammed amniotic fluid cells could treat vascular diseases

Weill Cornell Researchers discover a new effective approach for converting amniotic fluid-derived cells into endothelial cells to repair damaged blood vessels in heart disease, stroke, diabetes and trauma

NEW YORK (Oct. 18, 2012) — A research team at Weill Cornell Medical College has discovered a way to utilize diagnostic prenatal amniocentesis cells, reprogramming them into abundant and stable endothelial cells capable of regenerating damaged blood vessels and repairing injured organs.

Their study, published online today in Cell, paints a picture of a future therapy where amniotic fluid collected from thousands of amniocentesis procedures yearly, during mid-pregnancy to examine fetal chromosomes, would be collected with the permission of women undergoing the test. These cells, which are not embryonic, would then be treated with a trio of genes that reprogram them quickly into billions of endothelial cells — the cells that line the entire circulatory system. The new endothelial cells could be frozen and banked the same way blood is, and patients in need of blood vessel repair would be able to receive the cells through a simple injection.

If proven in future studies, this novel therapy could dramatically improve treatment for disorders linked to a damaged vascular system, including heart disease, stroke, lung diseases such as emphysema, diabetes, and trauma, says the study’s senior investigator, Dr. Shahin Rafii, the Arthur B. Belfer Professor in Genetic Medicine at Weill Cornell Medical College and co-director of its Ansary Stem Cell Institute.

“Currently, there is no curative treatment available for patients with vascular diseases, and the common denominator to all these disorders is dysfunction of blood vessels, specifically endothelial cells that are the building blocks of the vessels,” says Dr. Rafii, who is also a Howard Hughes Medical Institute investigator.

But these cells do much more than just provide the plumbing to move blood. Dr. Rafii has recently led a series of transformative studies that show endothelial cells in blood vessels produce growth factors that actively participate in organ maintenance, repair and regeneration. So while damaged vessels cannot repair the organs they nurture with blood, he says an infusion of new endothelial cells could.

“Replacement of the dysfunctional endothelial cells with transplantation of normal, properly engineered cultured endothelial cells could potentially provide for a novel therapy for many patients,” says study co-author Dr. Sina Rabbany, adjunct associate professor of bioengineering in genetic medicine at Weill Cornell. “In order to engineer tissues with clinically relevant dimensions, endothelial cells can be assembled into porous three-dimensional scaffolds that, once introduced into a patient’s injured organ, could form true blood vessels.”

Dr. Rafii says that this study will potentially create a new field of translational vascular medicine. He estimates that as few as four years are needed for the preclinical work to seek FDA approval to start human clinical trials to advance the potential of reprogrammed endothelial cells for treatment of vascular disorders.

As part of their study, the research team proved, in mice, that endothelial cells reprogrammed from human amniotic cells could engraft into an injured liver to form stable, normal and functional blood vessels. “We have shown that these engrafted endothelial cells have the capacity to produce unique growth factors to promote regeneration of the liver cells,” says the study’s lead investigator, Dr. Michael Ginsberg, a senior postdoctoral associate in Dr. Rafii’s laboratory.

“The novelty of this technique is that, from 100,000 amniotic cells — a small amount — we grew more than six billion new authentic endothelial cells within a matter of weeks,” Dr. Ginsberg says. “And when we injected these cells into mice, a substantial amount of them engrafted into regenerating vessels. It was remarkable to see that these cells went right to work building new blood vessels in the liver as well as producing the right growth factors that could potentially regenerate and repair injured organs.”

The Goldilocks of Cellular Reprogramming

To date, there have been many failed attempts to clinically produce endothelial cells that can be used to treat patients. Isolation of endothelial cells from adult organs so they can be grown in the laboratory is not efficient, according to Dr. Daylon James, study co-author and an assistant professor of stem cell biology in reproductive medicine at Weill Cornell Medical College. Attempts to produce the cells from the body’s master pluripotent stem cells have also not worked out. Experiments have shown that prototypical pluripotent stem cells, such as embryonic stem cells, which have the potential to become any cell in the body, produce endothelial cells but often grow poorly, and if not fully differentiated could potentially cause cancer. “Coaxing adult cells to revert to a stem-like state so they can then be pushed to form endothelial cells is, at this point, not clinically feasible, and ongoing studies in my lab are focused on achieving this goal,” says Dr.

James, who is also assistant professor of stem cell biology in obstetrics and gynecology and genetic medicine at Weill Cornell. Therefore, Dr. Rafii’s team searched for a new source of cells that they could turn into a vast supply of stable endothelial cells. They probed human amniotic fluid-derived cells, which some studies had suggested have the potential to become differentiated cell types, if stimulated in the right way — which no one had yet identified.

In their first experiments with these cells three years ago, Dr. Ginsberg used cells taken from an amniocentesis given at 16 weeks of gestation. Researchers found that amniotic cells are the “Goldilocks” of cellular programming. “They are not as plastic and unstable as endothelial cells derived from embryonic cells or as stubborn as those produced from reprogramming differentiated adult cells,” Dr. Ginsberg says. Instead, he says amniotic cells provide conditions that are just right — the so-called “Goldilocks Principle” — for producing endothelial cells.

But in order to make that discovery, the researchers had to know how to reprogram the amniotic cells. To this end, they looked for the genes that embryonic stem cells use to differentiate into endothelial cells. Dr. Rafii’s group identified three genes that are expressed during vascular development, all of which are members of the E-twenty six (ETS) family of transcription factors known to regulate cellular differentiation, especially blood vessel formation.

Next, they used gene transfer technology to insert the three genes into mature amniotic cells, and then shut one of them off after a brief and critical period of activity by using a special molecular inhibitor. Remarkably, 20 percent of the amniotic cells could efficiently be reprogrammed into endothelial cells. “This is quite an achievement since current strategies to reprogram adult cells result less than one percent of the time in successful reprogramming into endothelial cells,” says Dr. Rafii.

“These transcription factors do not cause cancer, and the endothelial cells reprogrammed from human amniotic cells are not tumorigenic and could in the future be infused into patients with a large margin of safety,” Dr. Ginsberg says.

The findings suggest that other transcription factors could be used to reprogram the amniotic cells into many other tissue-specific cells, such as those that make up muscles, the brain, pancreatic islet cells and other parts of the body.

“While our work focused primarily on the reprogramming of amniotic cells into endothelial cells, we surmise that through the use of other transcription factors and growth conditions, our group and others will be able to reprogram mouse and human amniotic cells virtually into every organ cell type, such as hepatocytes in the liver, cardiomyocytes in heart muscle, neurons in the brain and even chondrocytes in cartilage, just to name a few,” Dr. Ginsberg says.

“Obviously, the implications of these findings would be enormous in the field of translational regenerative medicine,” emphasizes study co-author Dr. Zev Rosenwaks, the Revlon Distinguished Professor of Reproductive Medicine in Obstetrics and Gynecology at Weill Cornell Medical College and director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. “The greatest obstacle to overcome in the pursuit to regenerate specific tissues and organs is the requirement for substantial levels of cells — in the billions — that are stable, safe and durable. Our approach will bring us closer to this milestone.”

“Most importantly, these endothelial cells could be reprogrammed from amniotic cells from genetically diverse individuals,” says co-author Dr. Venkat R. Pulijaal, director of the Cytogenetic Laboratory, associate professor of clinical pathology and laboratory medicine at Weill Cornell. What endothelial cells a patient receives would depend on their human leukocyte antigen (HLA) type, which is a set of self-recognition molecules that enable doctors to match a patient with potential donors of blood or tissue.

“Selecting the proper immunologically matched endothelial cells for each patient would be akin to blood typing. There are only so many varieties, which are well represented across the amniotic fluid cells that could be obtained, frozen and banked from wide variety of ethnic groups around the world,” Dr. Rafii says.

A patent has been filed on the discovery.

 

Other study co-authors from Weill Cornell Medical College include: Dr. Bi-Sen Ding, Dr. Daniel Nolan, Dr. Fuqiang Geng, Dr. Jason M. Butler, Dr. William Schachterle, Dr. Susan Mathew, Dr. Stephen T. Chasen, Dr. Jenny Xiang, Dr. Koji Shido and Dr. Olivier Elemento.

Dr. Rafii’s research is funded by the Howard Hughes Medical Institute, the National Heart, Lung, and Blood Institute, the Ansary Stem Cell Institute at Weill Cornell Medical College, the Empire State Stem Cell Board and New York State Department of Health grants, and the Qatar National Priorities Research Foundation.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University’s medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson’s disease, and most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

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