the sixth annual translational stem cell research ... · the new york stem cell foundation’s...

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Annals Meeting Reports

The Sixth Annual Translational Stem Cell ResearchConference of the New York Stem Cell Foundation

Caroline Marshall,1 Haiqing Hua,1,2 Linshan Shang,1 Bi-Sen Ding,3,1 Giovanni Zito,4,1

Giuseppe Maria de Peppo,1 George Kai Wang,2,1 Panagiotis Douvaras,1 Andrew A. Sproul,1

Daniel Paull,1 Valentina Fossati,1 Michael W. Nestor,1 David McKeon,1 Kristin A. Smith,1

and Susan L. Solomon1

1The New York Stem Cell Foundation, New York, New York. 2Columbia University, New York, New York. 3Weill Cornell MedicalCollege, New York, New York. 4Yale University, New Haven, Connecticut

Address for correspondence: Caroline Marshall, The New York Stem Cell Foundation, 163 Amsterdam Avenue, Box 309, NewYork, NY 10023

The New York Stem Cell Foundation’s “Sixth Annual Translational Stem Cell Research Conference” convened onOctober 11–12, 2011 at the Rockefeller University in New York City. Over 450 scientists, patient advocates, and stemcell research supporters from 14 countries registered for the conference. In addition to poster and platform presen-tations, the conference featured panels entitled “Road to the Clinic” and “The Future of Regenerative Medicine.”

Introduction

The New York Stem Cell Foundation’s (NYSCF) an-nual translational stem cell conference opened withtwo panels of experts discussing current progress intranslating stem cell research to accelerate cures forthe major diseases of our time. In the first panel“Road to the Clinic,” moderated by Lee Rubin, di-rector of translational medicine at the Harvard StemCell Institute and NYSCF scientific advisor, lead-ing experts from the pharmaceutical, biotechnol-ogy, and healthcare industries were joined by repre-sentatives from venture capital and grant-awardingfoundations to discuss how to transfer stem cellresearch from the laboratory into safe and effec-tive treatments. Panelists included Stephen Chang(New York Stem Cell Foundation), Scott John-son (Myelin Repair Foundation), Robert J. Palay(Cellular Dynamics International), and William A.Sahlman (Harvard Business School). The panel dis-cussed the latest research developments and thescientifically challenging path toward clinical tri-als. The second panel, “The Future of Regenera-tive Medicine,” composed of leading stem cell re-searchers and policy makers, discussed from theirdiffering perspectives the regulatory challenges fac-

ing researchers on the road to the clinic. Moderatorand chief executive officer of the New York StemCell Foundation Susan L. Solomon, and panelistsMahendra S. Rao (NIH Intramural Center for Re-generative Medicine), Craig B. Thompson (Memo-rial Sloan-Kettering Cancer Center), Marc Tessier-Lavigne (The Rockefeller University), and IrvingL. Weissman (Stanford University) examined thechanges in policy that will be needed to advance thedevelopment, evaluation, and approval of emergingstem cell treatments and regenerative medicine.

As in previous years, the second day of the confer-ence convened an international panel of researchersat the forefront of the stem cell field who presentedtheir work on diabetes, heart and muscles, cancerand blood disease, neurodegeneration, and pro-gramming/reprogramming.1,2 The panel includeda groundbreaking report on somatic cell nucleartransfer (SCNT), recently published in Nature byDieter Egli at the NYSCF laboratory.

In addition to a keynote address by IrvingL. Weissman, who discussed the latest devel-opments in cancer treatments using stem cells,the inaugural recipient of the NYSCF–RobertsonStem Cell Prize, Professor Peter J. Coffey (Univer-sity College London, and the London Project to

doi: 10.1111/j.1749-6632.2012.06481.x16 Ann. N.Y. Acad. Sci. 1255 (2012) 16–29 c© 2012 New York Academy of Sciences.

Marshall et al. NYSCF: Sixth Annual Conference

Cure Blindness) presented his forthcoming clini-cal trial using stem cells to treat age-related maculardegeneration.

NYSCF, in collaboration with Annals of New YorkAcademy of Sciences, is delighted to present this re-port; compiled by young stem cell scientists, it sum-marizes the excellent, groundbreaking progress instem cell research.

Diabetes

The opening speaker, Hans Snoeck (Mount SinaiSchool of Medicine), discussed the importance ofusing stem cells to generate thymus tissue. In vivo,the thymus is the immune organ in which T cell pos-itive and negative selection takes place. Thymus tis-sue derived in vitro has potential therapeutic appli-cations, such as enhancing T cell reconstitution afterallogeneic bone marrow transplantation. Human-ized mouse models can be created by transplantingthymus generated from human stem cells, whichare extremely valuable for studying human autoim-mune diseases, including type 1 diabetes.3 Snoeckshowed that when using activin A, BMP4, and basicfibroblast growth factor (bFGF), his group differen-tiated human embryonic stem cells into anterior en-doderm, from which thymic tissue is derived. Subse-quent treatment with Noggin and SB-431542 directsendoderm cells toward anterior foregut fate, withmore than 90% of the cells expressing SOX2.4 By ap-plying knowledge- and screening-based approaches,Snoeck’s group discovered combinations of variousfactors, including Wnt3A, fibroblast growth factor10 (FGF10), keratinocyte growth factor (KGF), andsonic hedgehog (SHH), that could further specifyforegut endoderm cells to become lung bud or pha-ryngeal endoderm cells. Notably, Snoeck pointedout that Wnt3A is crucial to prepattern the cellsfor lung development, and that retinoic acid in-duces lung fate partly through suppression of TBX1,a transcription factor necessary for pharyngealdevelopment.

Shuibing Chen (Weill Cornell Medical College;Fig. 1) summarized previous and ongoing effortsto generate pancreatic � cells from stem cells, in-cluding hypothesis-driven approaches based on an-imal models and in vitro studies that work wellfor the early stages of differentiation, specificallyduring the definitive endoderm and gut-tube endo-derm stage.5 In order to efficiently direct the cellsinto pancreatic progenitors and � cells, however,

she and her colleagues have been using discovery-driven screen approaches to search for the optimalconditions to facilitate this transition. After screen-ing with chemical libraries, they identified a smallmolecule, (–)-indolactam V, that can promote thegeneration of pancreatic progenitors by activatingprotein kinase C (PKC) signaling.6 Recently, Chen’sgroup screened for growth factors and cell lines thatinduce pancreatic progenitor and � cell generationand showed that mouse pancreatic endothelial cellsand a human endothelial cell line (AKT-HBVEC)significantly enhance the proliferation of pancreaticprogenitors in culture. Furthermore, Chen foundthat cell–cell contact is not required and the effectis mediated by factors that belong to the epidermalgrowth factor (EGF) family. Currently, the insulin-producing � cells derived in vitro are immature� cells, which do not display great response to glu-cose. Chen’s group is now seeking a cellular nichethat can accelerate the proliferation and/or matura-tion of � cells.

The final talk in this session was given by PedroHerrera (University of Geneva) who introduced theintriguing phenomenon of � cell to � cell transi-tion. Herrera’s group has developed new transgenicmodels allowing near-total � cell or � cell removal,specifically in adult mice; these mouse models en-able the study of pancreas regeneration after mas-sive cell loss. Herrera and colleagues showed that sixmonths after � cell removal, new � cells were re-generated. Around 20% of newly generated � cellsexpress both glucagon and insulin, hormones pro-duced by � cells and � cells, respectively. Using cell-tracing technology, Herrera and colleagues demon-strated that some of the newly formed � cells werederived from � cells.7 In contrast, they also observedthat when most of � cells are removed, the remaining2% of the normal � cell mass is enough to main-tain healthy and euglycemic mice.8 Taken together,these studies suggest that future diabetic therapiescould involve regenerating � cells via reprogram-ming adult � cells.

Cancer and blood disease

Shahin Rafii (Howard Hughes Institute and WeillCornell Medical College) opened this session anddescribed a recently identified instructive role ofpulmonary capillary endothelial cells (PCECs) insupporting lung regeneration.9 Previous work fromthe Rafii group established the novel concept that

Ann. N.Y. Acad. Sci. 1255 (2012) 16–29 c© 2012 New York Academy of Sciences. 17

NYSCF: Sixth Annual Conference Marshall et al.

Figure 1. Shuibing Chen (Weill Cornell Medical College and NYSCF-Robertson investigator) presents her work on derivingfunctional pancreatic endocrine cells from human pluripotent stem cells.

capillary endothelial cells (CECs) not only func-tion as passive conduits to meet metabolic de-mand, they also stimulate paracrine (angiocrine)growth factors to induce and sustain organ regen-eration.10–14 In bone marrow (BM)10–12 and liver,13

sinusoidal endothelial cells (SECs) constitute phe-notypically and functionally distinct populationsof cells. After partial hepatectomy, liver SECs—viaangiocrine production of hepatocyte growth factorand Wnt2 (a process defined as inductive angiogen-esis)—stimulate hepatocyte proliferation.13 Subse-quently, liver SECs undergo proliferative angiogene-sis to match the increasing demand for blood supplyin the regenerating liver. Likewise, after chemother-apy and irradiation, activated BM SECs inducehematopoiesis by angiocrine generation of Notchligands and insulin-like growth factor binding pro-teins (IGFBPs).10,12

To investigate the role of PCECs in support-ing lung regeneration, Rafii’s group generated aunilateral pneumonectomy (PNX) mouse modelby performing surgical resection of the left lunglobe. Without perturbing the vascular integrityof the remaining lobes, PNX induces significantgrowth of mass, volume, and physiological respira-tory capacity of the remaining lungs. This regener-ation process is due to neoalveologenesis, a processinvolving amplification of alveolar epithelial pro-genitor cells and PCECs. The phenotypic and op-

erational markers of mouse PCECs were definedas VE-cadherin+ VEGFR2+ FGFR1+ CD34+ ECs.They further demonstrated that PNX, through ac-tivation of VEGFR2 and FGFR1, induces PCECs ofthe remaining lobes to produce the angiocrine ma-trix metalloprotease MMP14. In turn, MMP14 pro-motes regenerative alveolarization by unmaskingcryptic EGF-like ligands that stimulate proliferationof epithelial progenitor cells. These studies under-score the instrumental role of endothelial-derivedangiocrine signals in instructing adult organ regen-eration. Selective activation of CECs, or increas-ing the generation of angiocrine factors in patients,would promote organ regeneration, thereby offer-ing therapeutic avenues for end-stage liver, lung, andhematopoietic diseases.

The second speaker of the session was VivianeTabar (Memorial Sloan-Kettering Cancer Center),whose laboratory focuses on understanding the al-terations within the brain stem cell niche that areresponsible for glioblastoma tumors. Previously, itwas demonstrated that a subpopulation of CD133+

cancer stem cells are responsible for the initiationof glioblastoma tumors.15 Tabar’s group discov-ered that CD133+ cancer stem cells not only ini-tiate the tumor but also generate new endothelialcells necessary for tumor self-maintenance.16 Thenewly generated cells presented a different geno-type when compared with normal blood vessel

18 Ann. N.Y. Acad. Sci. 1255 (2012) 16–29 c© 2012 New York Academy of Sciences.


Figure 2. Catriona Jamieson (University of California, San Diego) discusses the molecular evolution of leukemia stem cells duringthe session entitled “Cancer and Blood Disease.”

cells in the brain: the cells have an amplificationof the EGF receptor gene and the centromere ofchromosome 7, two typical mutations of differentglioblastomas variants.17 Tabar and colleagues iso-lated CD133+ cells from human glioblastoma sam-ples and cultured them in vitro to test their abilityto generate tumor vessels. Interestingly, they foundthat after seven days in vitro, CD133+ cancer stemcells differentiate into blood vessel cells expressingCD105, CD31, and CD34, which are typical en-dothelial markers in the brain. Tabar’s group con-firmed this in vivo by inoculating NOD/SCID micewith CD133+ GFP+ cells isolated from glioblastomatumors. Their results showed that gliobastomas thatdeveloped in NOD/SCID mice were characterizedby GFP+ blood vessels cells, suggesting that theCD133+ cancer stem cells were able to differenti-ate in vivo into endothelial cells necessary for tumorself-maintenance. Together, these data provide newinsights for the development of novel drugs or thera-pies for treating glioblastomas that aim at inhibitingthe endothelial transition of CD133+ cancer stemcells.

The third speaker of the session was Catri-ona Jamieson (University of California, San Diego;Fig. 2). Her talk explored the molecular evolu-tion of leukemia stem cells (LSCs) during progres-sion of chronic myeloid leukemia (CML) from thechronic phase (CP) to blastic phase (BP). Several

studies have shown that CML is characterized bythe Philadelphia (Ph) chromosome, which has aBCR/ABL1 rearrangement with enhanced kinaseactivity.18 Although it has been assumed that theBCR/ABL1 mutation occurs first in hematopoi-etic stem cells (HSCs) that are responsible for thedevelopment of the CML-CP phase,19 little is knownabout the molecular mechanisms that trigger thedisease to transition to the more severe CML-BPphase. Using RNA sequencing and nanoproteomicsapproaches, Jamieson identified splice variants andpoint mutations that commonly occur in all CMLtumor samples processed. These candidate genesare grouped into three classes: (1) genes involved inLSC aberrant self-renewal (such as Jak2), (2) genesinvolved in LSC dormancy (Shh), and (3) genesthat promote LSC survival (Bcl2). Using inhibitorsagainst these genes, Jamieson presented preliminaryin vitro results: (1) TG101348, a Jak2 inhibitor, whencombined with desatinib, a BCR/ABL1 inhibitor,arrested stem cell self-renewal ability; (2) Shh in-hibitors were able to reactivate the stem cell cycletransition from G0 to G1; and (3) sabutoclax, apan-inhibitor of the Bcl2 family, induced apopto-sis of LSCs, thus arresting the blast phase. Takentogether, these preliminary results support the pos-sible use of these target genes for development ofnovel therapeutics aimed at inhibiting CML-BP de-velopment.



Keynote address

The first invited keynote speaker was Irving L. Weiss-man (Stanford University; Fig. 3), whose work onhematopoiesis has been essential for defining thestages of development from hematopoietic stemcells (HSC) to their mature progeny. Many yearsof work on hematopoietic tissue, much of it ledby Weissman’s laboratory, has characterized pheno-typically and genotypically nearly every step of dif-ferentiation of stem cells to mature progeny. Someof this basic science knowledge has been essen-tial in understanding how normal hematopoieticcells become leukemic cells. For example, Weissmanand colleagues have shown that despite preleukemicprogression (such as EML1/ETO translocation) inHSCs, accumulation of further events in the progen-itor compartment is responsible for the formationof leukemic stem cells (LSC).20 Weissman’s groupidentified the cell marker CD47, which is upregu-lated in mouse and human acute myeloid leukemia(AML) stem cells and functions as a “don’t eat mesignal.” Weissman’s group demonstrated that ex-pression of CD47 on a human leukemia cell lineimproves tumor engraftment in immunodeficientmice due to evasion by CD47-expressing tumor cellsof phagocytosis.21 This suggests that cancer stem

cells can defeat programmed cell removal by upreg-ulating CD47 on their surface, which has led theway to a new anticancer treatment: blocking CD47with an antibody so that phagocytosis can elimi-nate tumor cells, for example, AML stem cells.22

Selective targeting of tumor cells by CD47 antibodyis explained by the simultaneous presence on tu-mor cells, but not on most normal cells, of calreti-culin, which acts as a prophagocytic signal.23 Fur-thermore, the combination of CD47 antibody withrituximab, a monoclonal antibody that engages Fcreceptors on NK cells and macrophages, has a syn-ergistic action that results in total elimination ofhuman non-Hodgkin lymphomas in mice.24 Fur-ther studies on bladder, ovarian, and breast cancerssuggest that different tumors use the same mecha-nism to escape immunosurveillance and can there-fore be attacked by anti-CD47 treatment. This is agreat example of translational research based on theevolution from basic science to the development ofnew drugs against human cancers.

Repairing our heart and muscles

The skeletal and cardiac muscle tissues constitute alarge portion of the human body and are character-ized by a set of different conditions that affect their

Figure 3. Irving L. Weissman (Stanford University and NYSCF Medical Advisory Board Member), Marc Tessier-Lavigne (TheRockefeller University and NYSCF Medical Advisory Board Member), Susan L. Solomon (CEO, New York Stem Cell Foundation),Mahendra S. Rao (Center for Regenerative Medicine, National Institutes of Health, and NYSCF Medical Advisory Board Member),and Craig B. Thompson (Memorial Sloan Kettering Cancer Center and NYSCF Medical Advisory Board Member) gather after apanel discussion entitled “The Future of Regenerative Medicine.”



functionality. The understanding of the molecularmechanisms governing the development, regenera-tion, and repair of these tissues is fundamental fordeveloping innovative therapeutic solutions for thetreatment of a large variety of medical conditionsassociated with disability and death.

During her presentation Margaret Buckingham(Institut Pasteur) addressed the role of satellite stemcells in skeletal muscle regeneration, as well as thefunction of Pax genes and downstream targets indifferent stages of tissue development and regener-ation. Satellite cells, quiescent cells found betweenthe basement membrane and the sarcolemma of in-dividual muscle fibers, undergo profound transcrip-tional changes upon activation. Microarray analy-sis of in vivo quiescent and activated cells revealshow satellite cells protect from oxidative damage,maintain quiescence, and are primed for activationwhen proper signals are provided.25 This findingsheds light on the importance of extracellular ma-trix degradation for satellite cell migration and acti-vation and demonstrates that upregulation of pro-teinases is crucial for optimal tissue regenerationin vivo. Buckingham’s group has focused on theexpression of Pax3 and its regulation of the myo-genic determination factor Myf5 during develop-ment and regeneration. Genetic analysis and chro-matin immunoprecipitation studies reveal that Pax3specifically binds a conserved sequence upstreamof Dmrt2 and regulates its expression. During tis-sue development, Dmrt2 regulates the early activa-tion of the Myf5 gene (Myf5), which plays a centralrole in the formation of the first skeletal musclein the somite.26 In contrast, Myf5 is already tran-scribed in satellite stem cells of adult muscle be-fore the onset of myogenesis, although translationinto a functional protein is repressed via bindingof microRNA-31 and subcellular sequestration ofthe microRNA–RNA complex in ribonucleopro-tein granules. Consistent with this expression ofmicroRNA-31, antagonists of microRNA-31 in an-imal models of injury promoted tissue regenera-tion and increased fiber size. Upon activation, thispost-transcriptional repression is released and cellsundergo myogenic differentiation.27 Buckinghamhighlighted the importance of silencing and seques-tering tissue-specific regulatory gene transcripts toensure rapid responses to tissue damage, and howsimilar control mechanisms may be involved in theregeneration of other somatic tissues.

Next, Deepak Srivastava (University of Cali-fornia, San Francisco) discussed his group’s ef-forts to develop novel therapeutic strategies forhuman cardiac disorders based on known devel-opmental pathways. By studying key molecularevents during heart development, Srivastava’s labhas identified a cascade of transcription factors andmicroRNAs that regulate early differentiation of car-diac progenitors and, later, their expansion into ven-tricular chambers.28–36 Many of these pathways canbe used to guide differentiation of pluripotent stemcells into cardiac, endothelial, and smooth musclecells that may be useful for regenerative medicine.One example of translating these observations intoregenerative approaches is the group’s recent successin direct reprogramming of cultured mouse post-natal cardiac fibroblasts (CFs) into cardiomyocyte-like cells using a combination of three core devel-opmental transcription factors, Gata4-Mef2C-Tbx5(GMT).37 These induced cardiomyocytes (iCMs)express cardiac-specific markers, have a globalgene expression profile similar to neonatal car-diomyocytes, and exhibit spontaneous Ca2+ flux,electrical activity, and contraction. Compared toiPSC reprogramming, reprogramming of CFs toiCMs with GMT occurs more rapidly (starting atday 3) and with a higher efficiency, up to 20%.Furthermore, Srivastava’s unpublished data con-firm that this technique also works in vivo. Usinga Cre-mediated lineage tracing technique, his grouphas demonstrated that resident CFs can be repro-grammed into iCMs through retrovirus-mediatedGMT transduction of mouse heart. Interestingly, thein vivo reprogramming efficiency was greater thanthat observed in vitro; and iCMs exhibited proper-ties, such as connexin 43 (Cx43) localization, ultra-structure under an electron microscope, action po-tential, and contractility, that closely resemble thenative adult cardiomyocytes, suggesting a morecomplete reprogramming than in vitro. Most im-portantly, reprogrammed iCMs found in the scarzone formed after myocardium infarction resultedin improved cardiac function. Given that CFs nor-mally compose over 50% of all the cells in the heart,these findings raise the possibility of reprogram-ming the vast pool of endogenous CFs into func-tional cardiomyocytes for regenerative purposes.

Michael Rudnicki (Ottawa Health Research In-stitute; Fig. 4) presented work on the identificationof signaling pathways that regulate the function of



Figure 4. Michael Rudnicki (Ottawa Health Research Institute,Canada) presents his latest work with molecular regulation ofmuscle stem cell function.

satellite stem cells in adult skeletal muscle. Satel-lite stem cells support growth, homeostasis, andregeneration of skeletal muscle tissue through asym-metric (apical–basal) and symmetric (planar) divi-sions.38 His laboratory has found that satellite cellsuniformly express the transcription factor Pax7.39

However, studies in mice have demonstrated that10% of cells within the Pax7 population are neg-ative for Myf5. Pax7+Myf5– cells were found togive rise to Pax7+Myf5+ cells through asymmet-ric division within the satellite cell niche, indi-cating a positional control of cell fate. In agree-ment with this, transplantation studies revealedthat the Pax7+Myf5+ cells are a subpopulation ofmyogenic progenitors that preferentially differen-tiate, whereas Pax7+Myf5– cells contribute to satel-lite niche repopulation.40 The ability of Pax7+Myf5–

cells to expand the satellite pool suggests thatthese cells may have therapeutic potential in treat-ing a large variety of degenerative disorders af-fecting the skeletal muscle system. Furthermore,Rudnicki described the mechanism through whichPax7 activity is regulated upon asymmetric celldivision, resulting in Myf5 transcription. Tandemaffinity purification and mass spectroscopy anal-ysis led to the identification of a set of cofactorsinteracting with Pax7, including the Wdr5-Ash2L-MLL2 histone methyltransferase complex, whichdirects chromatin modification and allows the tran-scription of myogenic determination genes.41 Simi-lar studies have led to identification of additionalPax7 interacting proteins, such as protein argi-nine N-methyltransferase-4 (CARM1/PRMT4).CARM1 binds Pax7 and regulates its function,through methylation of N-terminal arginines,

which is necessary for the recruitment of the Wdr5-Ash2L-MLL2 complex. Mutation of the methyla-tion sites in the Pax7 sequence reduces the abilityof Pax7 to upregulate Myf5 transcription, indicat-ing a direct control of myogenic specification byCARM1 in the satellite compartment. Rudnicki alsopresented new findings demonstrating the commonembryonic origin of brown fat and skeletal mus-cle. Isolated Pax7+Myf5+ satellite cells were foundto differentiate toward the adipogenic lineage whenappropriately stimulated. The transcription factorPDRM16 was found to control the bidirectionalfate switch between skeletal myoblasts and brownfat cells. Knockdown of PDRM16 in brown fat pre-cursor results in increased expression of myogenicgenes, whereas ectopic expression of PDRM16 inmyoblasts induces brown fat differentiation. Fur-thermore, immunopurification studies followed bymass spectroscopy demonstrate that PDRM16 in-teracts with PPAR-� ,42 recognized as a master tran-scriptional regulator of adipogenesis.43 These dataindicate a direct control of PDRM16 on brown fatdifferentiation.

Neurodegeneration and spinal cord injury

Steven Goldman (University of Rochester Medi-cal Center), the first speaker of the session enti-tled “Neurodegeneration and Spinal Cord Injury,”presented recent work on a new strategy to iso-late human oligodendocyte progenitor cells (OPCs)from fetal human brain.44 Following previouslypublished data from his lab, in which OPCs wereisolated by FACS based on the expression of thecell surface ganglioside marker A2B5, Goldman’sgroup identified that OPCs can be further enrichedby isolating cells expressing the receptor CD140a(PDGFRa), a subpopulation of the A2B5+ cells.45

CD140a+ cells from human fetal brain, depletedof neuronal- and astrocytic-specific markers, areable to migrate and myelinate neuronal axons whentransplanted into the hypomyelinated mouse brain.Myelination was faster and more efficient than thatobserved after transplantation of A2B5+ cells thatwere not further enriched for CD140a expression.This finding holds true when human CD140a+ cellsare transplanted in chemically induced demyeli-nating rat brains and when OPCs are producedfrom human iPS cells, though with variable effi-ciency rates. Finally, Goldman presented interest-ing unpublished data from experiments with the



shiverer mouse model following transplantation ofCD140a+ human OPCs into the mouse brains. Thecells gave rise to myelinating oligodendrocytes andastrocytes, and the brains were found to be chimeric,with >70% of the glial cells being of human origin(8 months posttransplantation), suggesting that hu-man donor cells outpace host-derived cells. Further-more, the transplanted cells retained a human phe-notype and function with high synaptic potentia-tion. Interestingly, Pavlovian-based behavioral testsshow that the chimeric mice are better at learningby association and can be conditioned to fear fasterthan their wild-type counterparts, a sign that thesemice might be “smarter.” In addition to allowing thestudy of basic biological interactions of human glialcells, this strategy provides a unique mouse modelin which to study diseases of the central nervous sys-tem, including human-specific infectious diseases.

In the second talk of the session, Paul Tesar (CaseWestern Reserve University) presented recently pub-lished work on the differentiation of mouse epiblaststem cells (EpiSCs) to OPCs.46 Tesar and his groupare attempting to produce pure populations of OPCsby directed differentiation, using the signals thatnormally play important roles during normal devel-opment of oligodendrocytes, and to identify the re-quired developmental transitions to produce func-tional OPCs. In the first stage, pluripotent EpiSCsare specified to the neuroectodermal lineage andcells are organized into typical neural rosette struc-tures by blocking the activin-nodal and BMP signal-ing pathways for four days. In the second stage, theneuroectodermal-like cells are patterned to region-specific neural precursor cells by addition of retinoicacid and SHH for one day. In the final stage, produc-tion of OPCs results from platelet-derived growthfactor (PDGF) and FGF signaling after an addi-tional five days. This ten-day differentiation pro-tocol results in a population of highly enriched cellsexpressing OPC-specific markers that display thetypical bipolar morphology of in vivo counterparts.Such mouse EpiSC-derived OPCs can be expandedfor at least eight passages—results consistent acrossfour independent EpiSC lines. After a further fourdays, the OPCs differentiate to highly specific ma-ture oligodendrocytes (lacking any neuronal or as-trocytic markers) that express basic myelin protein.The functionality of these OPCs was tested by inject-ing them into forebrain slices from the hypomyeli-nated shiverer mouse. In this context, the cells

produced oligodendrocytes that migrated andmyelinated neuronal axons in the host mouse braintissue. Tesar reported that similar experiments areunder way to find analogous methodologies thatwill robustly produce OPCs from human iPS cells.Finally, Tesar presented data (submitted) involvingdirect conversion of fibroblasts to OPCs, with a 10–15% efficiency; the OPCs could expand, differenti-ate to mature oligodendrocytes, and myelinate sec-tions of shiverer mouse brain.

Clive Svendsen (Cedars-Sinai RegenerativeMedicine Institute) presented two approaches totreating Huntingon’s disease (HD) and other neu-rodegenerative disorders. The first part of his talksummarized his lab’s work over the previous 14years using fetal brain tissue transplant approachesas a therapeutic intervention for HD and Parkin-son’s disease (PD) models.47,48 This method in-cludes isolation of human progenitors from the fetalcortex and then passage of the cells by a “choppingmethod” to insure cell–cell contact. After 20 pas-sages, these progenitors can differentiate, at a highpercentage, to astrocytes. Such astrocyte progenti-tors, injected into animal models, produce humanastrocytes that take 120 days to mature. The thera-peutic potential of these cells can be amplified usingex vivo gene therapy enabling the cells to producethe neuroprotectant glial cell–derived neurotrophicfactor. This combination is effective in modulatingthe deleterious effects observed in the N171–82Qmouse model of HD1. Svendsen described attemptsto move this approach to clinical application for avariety of neurologic disorders, including HD, ALS,macula degeneration, and stroke. The second partof Svenden’s talk described the progress of the iPSCStem Cell Consortium for Huntington’s disease,which is a collaboration between investigators frommultiple research institutions, including Svendsen’s,to generate and characterize HD patient-specificiPSCs. This unpublished work, funded by an NIHGrand Opportunities Grant, provides an opportu-nity for analysis of the HD iPSCs by groups withdifferent expertise, as well as independent valida-tion of experimental results by different laborato-ries. iPSCs have been generated from patients withdifferent levels of CAG repeats in the Huntingtongene. The number of CAG repeats dictates whethera person will develop HD and positively correlateswith age of onset.49 Various labs within the consor-tium have demonstrated numerous disease-related



phenotypes for neurons generated from multipleclones of higher CAG repeat iPSCs, including delaysin neuronal maturation, adhesion properties, ATPmetabolism, and cell death in response to stressessuch as acute pulses of glutamate and BDNF with-drawal. Sensitivity to glutamate is also associatedwith decreased ability to reset calcium homeosta-sis, which may explain why HD neurons are moresensitive to excitotoxic insults.

NYSCF-Robertson Prize lecture

During the NYSCF–Robertson Prize lecture, PeterJ. Coffey (University College London; Fig. 5) pre-sented an overview of the work he has done with theLondon Project to Cure Blindness to find a treat-ment for age-related macular degeneration (AMD).AMD affects roughly 14 million older adults in theUnited States and in Europe. Currently, dry AMD,which affects 90% of the clinical population, has noknown therapeutic treatment. Wet AMD, which af-fects 10% of the clinical population, can be treatedwith anti-VEGF therapy, but this therapy is expen-sive and time consuming, as patients must receivemonthly injections of drugs into the eye.

In wet AMD, blood vessels, which perfuse bloodinto the retina, protrude through a weakenedBruch’s membrane, the membrane dividing thechoroid and the retinal pigment epithelial (RPE)

cell layer.50 The protrusion of these blood vesselsinto the RPE cell layer compromises its functionand cuts off the nutrition and structural support itprovides for the photoreceptors, eventually leadingto detachment of the macula and vision loss.51 Inorder to treat wet AMD, Coffey and colleagues havedeveloped a macular translocation surgery in whichthe macula is reconstructed via its rotation. Macu-lar translocation resulted in 25% of patients gainingthree lines of acuity up to three years after surgery.52

However, this surgery is very complex and time con-suming, and the cost per patient is exceedingly high.Therefore, Coffey and colleagues attempted maculartranslocation with 360◦ retinotomy and autologousRPE–choroid patch graft, which has dramaticallyreduced costs as well as potential surgical complica-tions, such as trauma to the photoreceptors them-selves. However, RPE–choroid patch grafts werefound to be inferior to macular translocation alone,partially because exogenous RPE grafts lacked suffi-cient metabolic support and the graft membrane didnot allow sufficient attachment of the grated cells tothe Bruch’s membrane.53 To address the problem ofexogenous transplantation rejection, Coffey’s groupwas first able to develop RPE cells generated fromhESCs and successfully transplant these cells intothe RCS rat model with inherited retinal degenera-tion. His group showed that photoreceptors could

Figure 5. Peter J. Coffey (University College London, the London Project to Cure Blindness, and recipient of the InauguralNYSCF-Robertson Prize in Stem Cell Research) delivers a special keynote address on his use of human ESCs to cure age-relatedmacular degeneration.



be rescued using both electrophysiological and be-havioral tests, such as pattern discrimination andhead tracking after implantation of hESC-derivedRPE cells.54,55 Indeed, grafts of RPE cells derivedfrom iPS cells into RCS rats induce the short-termmaintenance of photoreceptors and significantly in-crease visual acuity.56 Coffey reported that experi-ments using choroid patch grafts from RPE-hESCsin pig retina result in the proliferation of functionalphotoreceptors with normal autofluorescence, in-dicating that the insertion of choroid patch graftsfrom RPE-hESCs into human eyes shows signifi-cant promise in the treatment of wet AMD. PhaseI/II clinical trials based on this research are proposedfor 2012.

Programming and reprogramming

Dieter Egli (New York Stem Cell Foundation; Fig.6), the first speaker of the session entitled “Program-ming and Reprogramming,” reported on two recentpublications aimed at generating patient-specificstem cells through the use of somatic cell nucleartransfer (SCNT). Egli first highlighted growing con-cerns about iPS cells, stressing the need for contin-ued work in SCNT.57–59 However, many labs havefailed to fulfill the potential of SCNT, thus posingthe question of whether these failures are because ofthe preliminary nature of the studies, or because ofan intrinsic issue with the human egg that preventsreprogramming.

Beginning with his experience at Harvard Univer-sity, Egli highlighted the issues of recruiting oocytedonors when only “altruistic donors” can be en-rolled.60 After moving to the New York Stem CellFoundation, Egli’s study continued in collaborationwith Columbia University Medical Center’s Centerfor Women’s Reproductive Care (CWRC), where,to date, 16 donors have participated. Initial experi-ments corroborated previous findings but also sug-gested that developmental failure was due to tran-scriptional dysfunction. Using microarray analysis,the expression profile of such failures closely resem-bled oocytes treated with transcriptional inhibitoraminitin, raising the following questions: (1) Is ar-tificial activation of the oocyte causing this arrest?This was not the case, as parthenogenetic blastocystscould be made. (2) Is oocyte manipulation causingthis arrest? This was answered no by demonstratingthat if the genome was removed and replaced intothe same oocyte, parthenogenetic blastocysts couldstill form. (3) Is the somatic cell genome interfer-ing with early development, or is it the removal ofthe oocyte genome? To answer this, a somatic cell(GFP labeled) was fused to an oocyte with an intactoocyte genome. Following activation, developmentto the blastocyst stage demonstrated GFP activationand, hence, that the somatic cell genome had partic-ipated in blastocyst development. Stem cells derivedfrom the blastocysts developed into all three germlayers and expressed markers typical of stem cells.

Figure 6. Dieter Egli (the New York Stem Cell Foundation) shares his groundbreaking work on reprogramming after nucleartransfer in the session entitled “Programming and Reprogramming.”



However, these stem cells were karyotypically ab-normal, with a triploid genome. To eliminate theissue of timing, the oocyte genome was removedat the first interphase, which led to developmen-tal arrest. Sequencing analysis of both gDNA andcDNA was undertaken with an allelic ratio of ∼0.6found in both, suggesting that the somatic genomewas as active as the oocyte genome. Analysis of geneexpression profiles of the stem cells showed thatthere was no preferential expression of either fi-broblast or stem cell genes, suggesting that no “so-matic memory” was present.61 This work suggeststhat the oocyte can reprogram the somatic genome,and further work is now under way to identify whatcauses developmental arrest following removal ofthe oocyte genome.

Alex Meissner (Harvard University; Fig. 7) be-gan his talk by referencing the same issues thatEgli raised concerning iPS cells. While acknowledg-ing that critical investigation is warranted, Meissnerpointed out that there is also a wide range in vari-ation among ES cells lines. These variations wereshown by methylation mapping, gene expressionprofiling, and use of a quantitative differentiationassay. Furthermore, while some iPS cell lines do notcluster with ES lines in these analyses, many do,suggesting that they are as useful as many ES lines.62

Meissner went on to discuss DNA methylation dy-namics and how to further our understanding ofwhere and when DNA methylation is used as a reg-ulatory mechanism. He described unpublished datathat highlights the critical role of DNA methyla-

tion during development. Zygotes from fertilizedmouse oocytes were collected at multiple times dur-ing development. It was initially found that althoughthere were few differences in global methylation pat-terns between E7.5 and adult tissue, analysis of theoocyte itself revealed a globally lower level of methy-lation than that in sperm. Following fertilization, acontinuous shift in demethylation (of the paternalgenome) is seen until E6.5 at implantation. Further-more, the inner cell mass (ICM) of the blastocystappears to differ greatly from that of the somaticgenome in which classically low CpG dense areasare highly methylated. It was also found that for anumber of genes, including Dnmt1, separate mater-nal and somatic methylation patterns exist. Until theeight-cell stage of development, the somatic Dnmt1CpG island is highly methylated before switchingto a demethylated state, with the opposite beingtrue for the maternal version. From unpublished,ongoing, collaborative work with Egli, the initialanalysis of mouse nuclear transfer zygotes appearsto show that nuclear transfer blastocysts show com-parable global demethylation to that seen in zygotes.It appears, however, that similar to sperm, the oocyteis capable of removing some methylation from pre-viously highly methylated areas, although a num-ber of regions remain as methylated as in the so-matic cell. Therefore, remodeling by the oocyte doestake place; however, not all regions are remodeledequally.

Kevin Eggan (New York Stem Cell Foundationand Harvard University) ended the programming

Figure 7. Alex Meissner (Harvard University) discusses his progress in epigenetic reprogramming.



and reprogramming session by discussing his re-cently published work describing the direct con-version of mouse and human fibroblasts into in-duced motor neurons (iMNs) by a process referredto as transdifferentiation.63 The purpose of this studywas to generate amyotrophic lateral sclerosis (ALS)disease-specific motor neurons by transdifferentia-tion, which subsequently could be compared to sim-ilarly derived control motor neurons. Eggan, whopioneered the first ALS-specific iPS cells that couldmake disease-specific motor neurons,64 suggestedthat iMNs, owing to their significantly faster gen-eration time, could provide a quicker preview ofdisease-specific phenotypes than iPS approaches.Eggan’s group first attempted to generate iMNsby virally overexpressing eight transcription factorsalone, or in combination, known to be importantfor either the motor neuron differentiation processor in the mature motor neuron itself. This approachwas unsuccessful in generating iMNs from fibrob-lasts obtained from HB9:GFP mice (which pro-duce GFP-fluorescing motor neurons). However,when Eggan’s group combined this strategy with thethree transcription factors used by Marius Wernig’sgroup to create more general neurons from fibrob-lasts (iNs),65 they successfully generated iMNs. Thiscould be reduced to a six or seven transcription fac-tor cocktail, and could also be used to create iMNsfrom human fibroblasts. Similar to iNs,66 the trans-differentiation process to iMNs does not appearto involve a neural progenitor intermediate. iMNswere shown to resemble bona fide motor neuronsby a variety of criteria, including gene expressionstudies, electrophysiological properties, formationof cholingeric synapses with muscle cells generatedfrom the C2C12 cell line, and implantation intothe developing chick spinal cord with subsequentappropriate axonal migration to peripheral targets.Eggan finished his talk by showing preliminary un-published data suggesting that human iMNs pre-pared from ALS patients with genetic forms of thedisease demonstrate increased electrical excitabilitycompared to control iMNs, which could predisposethe former to increased sensitivity to excitotoxicinsults.

Conclusion

NYSCF’s sixth annual meeting convened leaders instem cell research, both senior and innovative youngscientists, providing attendees with novel scientific

presentations that focused on a wide variety of dis-eases and techniques. The speakers, including twoscientists from NYSCF’s inaugural class of NYSCF-Robertson investigators, gave conference partici-pants a first-hand look at unpublished and recentlypublished pioneering research. The “Seventh An-nual Translational Stem Cell Research Conference”will take place on October 10–11, 2012.

Acknowledgments

New York Stem Cell FoundationSixth Annual Translational Stem Cell Research

ConferenceCo-chairsLee Goldman, MD, MPH, Columbia University

Medical CenterAntonio M. Gotto Jr., MD, DPhil, Weill Cornell

Medical CollegeDouglas A. Melton, PhD, Harvard UniversityAllen M. Spiegel, MD, Albert Einstein College of

MedicineMarc Tessier-Lavigne, PhD, The Rockefeller

UniversityCraig B. Thompson, MD, Memorial Sloan-Kettering

Cancer CenterScientific Co-chairsMoses V. Chao, PhD, Skirball Institute of

Biomolecular MedicineZach W. Hall, PhD, The New York Stem Cell

FoundationIhor Lemischka, PhD, The Mount Sinai School of

MedicineDan R. Littman, MD, PhD, Skirball Institute of

Biomolecular MedicinePrincipal SponsorRobertson FoundationCo-sponsoring InstitutionsAlbert Einstein College of MedicineColumbia University Medical CenterHelen and Martin Kimmel Center for Stem Cell

Biology, New York University School of MedicineMount Sinai School of MedicineTri-Institutional Stem Cell Initiative:

• Memorial Sloan-Kettering Cancer Center• The Rockefeller University• Weill Cornell Medical College

Conflicts of interest

The authors declare no conflicts of interest.



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