iPS-derived intestinal organoids
iPS-derived intestinal organoids

What are iPSCs?

Induced pluripotent stem cells are derived from the donated skin or blood cells of adults and, with the reactivation of four genes, are reprogrammed back to an embryonic stem cell-like state. Like embryonic stem cells, iPSC cells can be differentiated toward any cell type in the body, but they do not require the use of embryos.

Since the original discovery by Nobel Prize Awardee Shinya Yamanaka, our knowledge about iPSC cells has exponentially expanded.

What can we learn from iPSCs?

As an indefinitely self-renewing cell type that mimics an embryonic state in the dish, iPSCs can help us understand molecular processes in embryonic development. Research in developmental biology is a particular focus of CReM investigators, motivated by the philosophy that understanding how tissues form during normal development is the key to understanding stem cell biology and mechanisms regulating cell fate and lineage specification.

Ultimately, an important goal of the CReM is the clinical application of stem cells to better understand and treat human diseases. iPSCs have immense potential to benefit patients with degenerative diseases such as cystic fibrosis, alpha-1 anti-trypsin deficiency, sickle-cell anemia, liver cirrhosis, pulmonary fibrosis, inflammatory bowel disease and others. Many of these diseases are inherited conditions caused by only a single mutation in the patient’s genome. Current research in the CReM focuses on technology to correct these mutations in iPSCs from individuals with these illnesses and to subsequently differentiate them toward tissues of interest that could be used to better understand the mechanisms of disease and in the future for cell replacement therapies. Because the replacement tissues would originate from the patient in need, rejection by the patient’s immune system is avoided.

iPSC-derived lung epithelial cells
iPSC-derived lung epithelial cells
CReM Tissue Culture Room
CReM Tissue Culture Room

Our state-of-the-art facilities

The Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center is a physically contiguous state-of-the-art facility housed in expansive space located on the Boston University Medical Campus. The Center’s footprint consists of 16,000 sq ft of wet bench space and 6,000 sq ft of offices.

Here, seven research labs, physicists, and bioinformatics researchers work together, synergistically in a multi-disciplinary approach to advancing stem cell biology and regenerative medicine. The heart of the physical CReM resides in 1resides in five dedicated stem cell culture rooms, containing twenty biosafety tissue culture hoods, thirty incubators, bioreactors and several sophisticated microscopes with multi-channel imaging capabilities. The CReM also contains a dedicated small animal operating room, chemical room, radioactive room and its own cellular analysis room with a newly installed Nikon Ni-E Motorized Multi-channel upright microscope and two flow cytometers.

Research Programs

The Center for Regenerative Medicine (CReM) is dedicated to advancing regenerative medicine for the sake of patients — particularly those suffering from diseases seen at Boston Medical Center, the teaching hospital of Boston University School of Medicine.
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The mission of the CReM’s Program in Lung Stem Cell Biology is to develop the world’s leading lung regeneration initiative by advancing the basic science that will result in personalized therapeutics to prevent and cure diseases or injuries of the lung, including emphysema, ARDS, pulmonary vascular disease, cystic fibrosis, additional adult and pediatric genetic lung diseases, and pulmonary fibrosis. We seek to understand the essence of how lung cells decide and remember their fate, thereby revealing the basic mechanisms by which diseased or dysplastic lung cells can be returned to normalcy. We study the genetic and epigenomic landscapes of lung cell fate, the mechanisms that establish those fates, and the stem cell populations that can be harnessed to produce those fates.

Here at the institution that invented the principle spirometric measure of lung function (FEV1), founded on a half century of internationally recognized leadership in basic and clinical lung research, we utilize BU-patented reprogramming technology for the production and differentiation induced pluripotent stem (iPS) cells and we examine the biology and embryonic development of endogenous lung progenitors. Utilizing the world’s largest lung disease-specific stem cell bank, the BU/BMC iPS cell bank, we engineer stem cells for next generation clinical trial simulation, personalized therapeutic model predictions, high throughput drug screenings, and cell-based therapies of lung diseases. Ultimately our initiative’s discoveries seek to culminate in the de novo generation of all the lung lineages required to generate transplantable, tissue-engineered cells, complex tissues or entire organs needed to accomplish successful lung regeneration.

To read more about these programs, please click on the links for each of our labs—all located on a single floor of our 16,000 square ft CReM stem cell facility.

Kotton Lab
Wilson Lab
The Hawkins Lab

At the CReM we have a long standing interest in the study of the Gastrointestinal tract, using human iPSC to better understand intestinal lineage specification as well as using patient-specific iPSC for disease modeling. We were one of the first to establish a novel protocol for the differentiation of iPSC into Human Intestinal Organoids (HIOs) devoid of mesenchymal components while describing a novel CDX2-GFP knock-in reporter line allowing real-time visualization of intestinal specification (Mithal et al, 2020). We are using these HIOs to model several infectious diseases, including SARS-CoV-2 (Mithal et al, 2021) as well as Ebola virus infection. In collaboration with clinicians at Boston Medical Center, we were able to establish iPSC libraries from patients with hereditary forms of colorectal cancer, including Familial Adenomatous Polyposis (FAP) as well as Lynch Syndrome, and we have now created one of the largest libraries of Crohn’s-specific iPSC.

To learn more, please click on the webpages of one of our investigators studying gastrointestinal stem cells and gastrointestinal epithelial injury and repair:

Mostoslavsky Lab
BMC Center for Digestive Disorder

Mission Statement

The developmental hematopoiesis component of the Center for Regenerative Medicine (CReM) consists of a team of basic, translational and clinician scientists conducting state-of-the-art research centered around the induced pluripotent stem cell (iPSC)-based modeling of blood cell development, hematopoietic stem cell (HSC) biology and the differentiation of these cells into defined lineages. Insights into these biological processes can then be harnessed to further our understanding of blood-borne diseases and to create tools that will help us screen and validate novel treatment options. The long-term objectives of our work are to develop gene and cell-based therapies aimed at combating blood-borne diseases such as sickle cell anemia, amyloidosis, and various thrombotic disorders.

Background and Interests

Hematopoietic stem cells (HSC) are a rare and renewable population of cells which reside in the bone marrow of all mammals and are known to give rise to all of the differentiated cells of the adult peripheral blood. The HSC biology component of the CReM focuses upon the identification, study and manipulation of the stem cell compartment and resulting hematopoietic cells of multiple tissue types at various stages of both murine and human development.
Differentiation of all blood cell lineages is a tightly regulated process, the disruption of which has many consequences. The definition of the molecular mechanisms that control these processes has been hampered by the lack of model systems in which sufficient numbers of primary hematopoietic cells can be grown and differentiated into committed blood lineages. Reprogramming human somatic cells and their differentiation into hematopoietic cell subsets provides an unprecedented opportunity to study development and disease in a patient-specific fashion using primary cells. Insights gained from these studies include a better understanding of developmental hematopoiesis and subject-specific revelations in blood-borne diseases such as sickle cell disease (the CReM houses the world’s largest library of SCD-specific iPSC lines), amyloidosis, and various thrombotic disorders. The iPSC technology developed by the group allows for the creation of advanced disease models of the blood and may allow for the production of “custom” stem cell-derived blood products for human transfusion such as red blood cells, platelets, and T cells for cell-based therapies that match the patient’s immunologic profile.

Center of Excellence in Sickle Cell Disease
BU Amyloid Treatment and Research Program
Murphy Laboratory

The Mission

The mission of the BULB program led by Dr. Valerie Gouon-Evans is to decipher the mechanisms driving liver development and disease with a specific focus on discovering novel regenerative liver therapies. The Program brings together multiple cross campus researchers/entities including basic scientists and physician-scientists, with clinicians from the Boston Medical Center (BMC) Section of Gastroenterology, the BU/BMC Alpha-1 Center, and the Boston University (BU) Amyloid Treatment and Research Program. The Program’s best-known foci to date have been the monogenetic chronic liver diseases associated with alpha-1 antitrypsin deficiency (AATD), familial amyloidosis, or hemochromatosis in addition to non-genetic related acute and chronic liver diseases. An incredible asset of the BULB program is the inclusion of outside collaborator members from our neighbor institutions MIT and UMass Chan Medical School in Worcester as well as from Cornell University in New York and Pittsburgh University.

Research interests

Human induced pluripotent stem cell (hiPSC)-derived hepatocyte-like cell (HLC) platform: Understanding liver diseases and developing liver cell therapy
Scientists from the program are currently modeling genetic liver diseases or infectious liver diseases in vitro to decipher liver disease mechanisms by directed differentiation of induced pluripotent stem cell lines from patients into HLCs. When applicable, the mutated liver gene is typically corrected through gene editing technologies, such as CRISPR/Cas9, to produce patient-specific edited HLCs. Various mouse models mimicking acute and chronic human liver diseases are currently established to test and validate the usefulness of human iPSC-derived HLCs to treat liver diseases.
Keywords: hiPSC; gene editing; in vitro direct differentiation of hiPSC into HLCs; hiPSC-based liver organoids; liver organ-on-a-chip; synthetic biology; hiPSC-based liver disease modelling; liver fibrosis; AATD; familial amyloidosis; hemochromatosis; Ebola infection modelling; HLC and primary human hepatocyte therapy; nucleoside modified mRNA complexed in lipid nanoparticles.
Labs: Gouon-Evans, Wilson, Mostoslavsky, Murphy, Hollenberg, Soto-Gutierez, Weiss and Schwartz.

Liver disease and regeneration
Research from the program aims to decipher the cellular and molecular mechanisms leading to liver disease and regeneration to ultimately develop regenerative therapies.
Keywords: mouse and zebrafish models of acute and chronic liver injuries; fatty liver; liver fibrosis; acetaminophen overdose; alcoholic liver disease; cholestatic liver disease; hepatocellular carcinoma, liver inflammation; metabolic zonation; hepatocyte growth factor; epidermal growth factor; Wnt; YAP; thyroid hormone; growth hormone; epigenetic; in vivo hepatocyte reprogramming; nucleoside modified mRNA complexed in lipid nanoparticles.
Labs: Gouon-Evans, Wilson, Hollenberg, Waxman, Mandrekar, Monga, Shin, Soto-Gutierez and Schwartz

Liver regeneration via activation of cholangiocyte-derived liver progenitor cells (LPC)
Although the liver has a robust ability to self-regenerate through the proliferation of mature hepatocytes, in the case of acute or chronic liver injury, proliferation of mature cells is exhausted. Liver repair in most acute and chronic liver diseases in human is thus associated with expansion of LPCs in a process termed ductular reaction that includes proliferation of cholangiocytes, thought to contribute to liver regeneration. Scientists from the Program are currently investigating the mechanisms triggering LPC-mediated repair and testing tools to activate LPCs to further promote cholangiocyte-mediated innate liver repair.
Keywords: mouse and zebrafish models of acute and chronic liver injuries; cholangiocyte-to-hepatocyte conversion; liver progenitor cells; vascular endothelial growth factor A; Wnt; EGF receptor; Farnesoid X receptor; nucleoside modified mRNA in lipid nanoparticles.
Labs: Gouon-Evans, Shin and Monga

Investigation of the lung-liver axis during pneumonia
The Quinton lab’s research investigates the lung immunity and the biological signals that dictate pneumonia outcome and susceptibility. The lab elucidates the cells and signals both inside and outside of the lungs via the lung-liver axis responsible for mounting immune responses that are effective and appropriate during pneumonia.
Keywords: lung-liver axis, pneumonia, immune response
Labs: Quinton

Benefits to being a BULB member

The BULB program’s monthly hybrid meetings (in-person and zoom) offer a friendly environment to present unpublished data in a Work-In-Progress format. Presently, the BULB program members are directly appointed at BU/BMC (inside members) or are recruited from outside institutions (outside members) through collaborations with the inside members. To become a BULB member, please email Dr. Gouon-Evans at valerige@bu.edu.

Scientific Stimulation

  • Continued education in liver field
  • Identify common resources and technologies as well as new technologies in the area of liver (hiPSC bank from the CReM, protocols, lentiviruses, mouse colonies…).
  • Network with prominent labs to inform them of the lab’s research that is ongoing in the liver area at BU and collaborative institutions.
  • Career advancement of senior trainees: Opportunity for the BULB’s senior trainees to meet with outside PIs as potential postdoctoral host labs.
  • Increase women and URM representation in liver sciences.
  • Collaborative research leading to collaborative grant applications.
  • Collaborative research leading to collaborative manuscripts.
  • Interact with our national network of liver research Centers and collaborators: BULB, Pittsburgh Liver Research Center, etc.

Travel Award for trainees: Competitive travel award: up to $2,000 per trainee per lab/year. 5 awards will be given per year. Please acknowledge the BULB program at meetings when awarded a Travel Award.

PI BULB Members
Inside Members
Dr. Valerie Gouon-Evans (BULB program Director, BU BMC, CReM, Dept of Medicine, Gastroenterology Section)
Dr. Andrew Wilson (BU, CReM, Dept of Medicine, Pulmonary, Allergy, Sleep & Critical Care Medicine Section)
Dr. Gustavo Mostoslavsky (BU BMC, Dept of Medicine, Gastroenterology Section)
Dr. George Murphy (BU BMC, Dept of Medicine, Hematology & Medical Oncology Section)
Dr. Anthony Hollenberg (BU BMC, Chair of Dept of Medicine)
Dr. David Waxman (BU, Dept of Medicine, Gastroenterology Section and Dept of Biomedical Engineering)
Dr. Arpan Mohanty (BU BMC, Dept of Medicine, Gastroenterology Section)
Dr. David Nunes (BU BMC, Dept of Medicine, Gastroenterology Section)
Dr. Robert Lowe (BU BMC, Dept of Medicine, Gastroenterology Section)
Dr. Gareth Morgan (BU, Dept of Medicine, Amyloidosis Center)
Dr. John Berk (BU, Dept of Medicine, Amyloidosis Center)
Dr. Tatiana Prokaeva (BU, Dept of Medicine, Amyloidosis Center)

Outside Members
Dr. Lee Quinton (UMass Worcester, Dept of Medicine; BU BMC, Adjunct Professor, Dept of Medicine)
Dr. Pranoti Mandrekar (UMass Worcester, Dept of Medicine, Gastroenterology Division)
Dr. Paul Monga (Pittsburgh University, Dept of Medicine, Director of Liver Research Center)
Dr. Donghun Shin (Pittsburgh University, Dept of Developmental Biology)
Dr. Alex Soto-Gutierez (Pittsburgh University, Dept of Pathology)
Dr. Ron Weiss (MIT, Dept of Biological Engineering)
Dr. Robert Schwartz (Sanford I. Weill Medical College of Cornell University, Dept of Medicine)

LINKS:
Center for Regenerative Medicine
Pittsburgh Liver Research Center
BU Alpha 1 Center
BU Amyloidosis Center

The Biomedical Engineering component of the Center for Regenerative Medicine features cross-disciplinary collaborations between stem cell biologist and biomedical engineers across the bredth of Boston University and Boston Medical Center, including faculty from our renowned BU College of Engineering. We focus on reconstituting organ structure and function using a variety of stem cells, organoids, synthetic biology approaches, and engineered tissue platforms. From novel scaffolds to bioreactors to nanotechnologies for editing or delivering stem cells in vivo to engineered “organ on chip” platforms we pursue state-of-the approaches for engineering regeneration. We are also developing novel technologies to monitor the function of engrafted stem cells in vivo after transplantation. One of our marquee programs on engineered regeneration is BU’s Multicellular Design Program, a cross-campus collaboration between the CReM and the College of Engineering’s Biological Design Center, funded by the Rajen Kilachand Fund for Life Sciences and Engineering, as part of a generous gift from Boston University’s trustee Rajen Kilachand (Questrom’74, Hon.’14)

Please click below for more information about our investigators.

Kotton Lab
Christopher Chen
Joyce Wong, PhD
Bela Suki, PhD
Wilson Wong
Mo Khalil
BU Biological Design Center 
Multicellular Design Program

The CReM’s Neurodegerative Disorders Program aims to develop pioneering work towards understanding cellular and molecular mechanisms of neurodevelopmental and neurodegenerative disorders in the context of rare diseases. Our program currently hosts two main research avenues:

Creutzfeldt Jakob Disease
Creutzfeldt-Jakob disease (CJD) is an extremely rare, progressive and transmissible neurodegenerative disorder associated with the accumulation of misfolded prion protein in the central nervous system. CJD is thought to affect about one in a million people worldwide per year.

Led by Dr. Gustavo Mostoslavsky, the CReM’s Neurodegenerative Disorders Program established the largest iPSC library of E200K mutant cells from individuals with CJD. We are utilizing their differentiated motor neurons to study expression of normal vs mutant prion protein and the mechanisms behind Prion-mediated neural toxicity. We have also created syngeneic CRISPR corrected lines and we are establishing brain organoids from normal and mutant cells to study the role of abnormal prion protein in these organoids.

Kabuki Syndrome
Kabuki Syndrome (KS) is a rare autosomal dominant disorder that affects several systems and organs in varying degrees of severity. About 90% of KS patients have varying manifestations neurodevelopmental disorders (NDD) greatly affecting quality of life for KS children and their families. Approximately 70% of KS patients have a mutation in the histone methyl-transferase KMT2D enzyme involved in epigenetic regulation, however, the cellular and molecular mechanisms leading NDD phenotypic variability are unknown.

The CReM’s Neurodegenerative Disorders Program recently recruited Dr. Angie Serrano whose main research goals are to discover the mechanisms and pathways by which distinct mutations in chromatin modifiers like KMT2D lead to a range of neurodevelopmental disorders, and also to test pharmacological approaches to ameliorate them. Dr. Serrano’s research uses the experimental versatility and high-throughput capabilities of Kabuki Syndrome zebrafish models and the translatability of KS patient iPSC-derived brain organoids to understand the novel roles of KMT2D during neurogenesis and to uncover the molecular mechanisms of NDD. The long-term objective is to develop possible therapeutic interventions to ameliorate neurodevelopmental disease in KS children.

Please click below for more information about our investigators.

Mostoslavsky Lab
Serrano Lab

The Vascular Biology/Endothelial Injury and Repair Program’s mission is to understand vascular patterning and functional abnormalities in three main areas:
• pulmonary vascular diseases
• mitochondrial genetics in cardiovascular pathophysiology
• complex multisystemic rare diseases
We use a combination of patient-derived iPS cells, research organisms and system biology to understand the genetic, epigenetic and epidemiologic nature of the vascular component of these diseases.

Pulmonary vascular diseases - Kotton Lab
Pulmonary vascular diseases include idiopathic pulmonary arterial hypertension, familial pulmonary arterial hypertension, and congenital anomalies of cardiopulmonary vascular development such as alveolar capillary dysplasia. The CReM has established a biorepository of iPSCs generated from patients and their families impacted by these diseases. Our research programs focus on developmental directed differentiation of these iPSCs into mesodermal and vascular lineages, such as endothelium and vascular smooth muscle to build models of disease in the dish or to prepare cells or engineered tissues for future transplantation strategies to reconstitute vascular function in vivo.

Mitochondrial genetics in cardiovascular pathophysiology - Fetterman Lab
Our research program utilizes trans-disciplinary approaches to advance our understanding of the role and mechanisms of mitochondrial genetics in cardiovascular pathophysiology. To do so, we evaluate mitochondrial genetics and biology at the population level through genetic epidemiology and systems biology approaches, at the cardiovascular tissue level through rapid autopsy and biopsy samples, and through the creation of cardiovascular cells from human iPSCs. We leverage the existing Framingham Heart Study iPSC biorepository in the CReM to create cardiomyocytes through a mesodermal lineage to study the interactions of the mitochondrial and nuclear genomes on cardiomyocyte metabolism and function. Our goal is to identify the mechanisms for how mitochondrial genetic variation contributes to the development of cardiovascular diseases.

Vascular abnormalities in rare diseases - Serrano Lab
Cardiovascular anomalies are a frequent clinical manifestation in several multisystemic rare diseases. We aim to uncover the molecular mechanisms regulating cell differentiation of endothelial cells and vascular patterning anomalies of rare diseases with an epigenetic basis during development and disease. At the CReM, we combine the experimental versatility and high-throughput capabilities of zebrafish and the translatability of patient-specific iPSCs research to model rare diseases. While our current focus is Kabuki Syndrome (KS) type I, we plan to expand our research program to KS type II, KAT6A and KAT6B related disorders.
Our long-term goal is to develop early strategies and therapeutic interventions to ameliorate the vascular component of these diseases.

Kotton Lab
Fetterman Lab
Serrano Lab

Rare individuals with exceptional longevity suggest we have within us the potential for longer, more healthful lives. In the last decade, several studies have provided evidence that many centenarians (>100 years of age) and their offspring delay or escape aging-related diseases, such as cancer, cardiovascular disease, and Alzheimer’s disease, while markedly delaying disability. These findings provide an unexpected and promising entry point for understanding healthful aging and the mechanisms that limit or embolden disease.

At the CReM, we combine innovative, exceptional longevity (EL)-specific induced pluripotent stem cell (iPSC)-based models capable of recapitulating human development with next generation sequencing approaches to identify the transcription factors, signaling pathways, and protein interaction networks that are linked to longevity and act to sustain cellular integrity and functionality during acute disease and in old age. The iPSC lines we have created will act as an unlimited resource of exceptional-longevity-specific biomaterial that can be used to fuel the study of aging and will also allow for the development of novel therapeutics against aging-related disease. This work has the potential to revolutionize our thinking concerning regenerative medicine and the aging process while unlocking a detailed roadmap to healthful living, disease resistance and longevity.

Please click below for more information about our investigators.

Murphy Lab

Faculty List

Lung Stem Cell and Developmental Biology

Darrell Kotton (MED/Pulmonary)
Andrew Wilson (MED/Pulm)
Finn Hawkins (MED/Pulm)
Konstantinos Alysandratos (MED/Pulm)
Andrew Berical (MED/Pulm)
Joseph Kaserman (MED/Pulm)
JC Jean (MED/Pulm)
PJ Maglione (MED/Pulm)

Hematopoietic Stem Cell Biology and Blood Disorders

George Murphy (MED/Heme-Onc)
Martin Steinberg (MED/Heme-Onc)
Lou Gerstenfeld (Orthopedic Research)
Kim Vanuytsel (Med/Hem-Onc)
Camille Edwards (Med/Hem-Onc)
Ruben Dries, PhD (Med/Hem-Onc)
Elliott Hagedorn, PhD (Med/Hem-Onc)
Katya Ravid, DSc (Med/Evans Center IBR)

Physics

Pankaj Mehta (Physics)
Andrei Ruckenstein (Physics)

Vascular Biology/Endothelial Injury and Repair

Jessica Fetterman (MED/Vascular Biology)
Angie Serrano (MED/Vascular Biology)
Darrell Kotton (MED/Pulmonary)

Gastrointestinal Stem Cell Biology

Gustavo Mostoslavsky (MED/GI)
Valerie Gouon-Evans (MED/GI)
David Waxman (Biology)

Biomedical Engineering

Bela Suki (BME)
Wilson Wong (BME)
Chris Chen (BME)
Joyce Wong (BME)
Ahmad (Mo) Khalil (BME)

Biochemistry

Bob Varelas (Biochemistry)
David Harris (Biochemistry)

Liver

David Waxman (Biology)
Gustavo Mostoslavsky (MED/GI)
Valerie Gouon-Evans (MED/GI)
Andrew Wilson (MED/Pulm)
George Murphy (MED/Heme-Onc)

CReM Labs

We are a dynamic group of investigators passionate about stem cells, developmental biology and regenerative medicine. Our 60 lab members come from more than 15 different countries and work together in a physically contiguous Center occupying the entire floor of an expansive state-of-the-art laboratory facility at 670 Albany Street, our home since 2013. Here we work together to fulfill our mission: “Advancing science to heal the world”

Gouon-Evans Lab

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