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CReM receives $2.7 million grant to create a stem cell repository

November 10, 2014 Monday

The Center for Regenerative Medicine (CReM) at Boston University and Boston Medical Center has been awarded a grant to establish a first-of-its-kind stem cell repository that researchers from across the country can access for free. Funded through a five-year, $2.7 million federal grant from the National Heart, Lung, and Blood Institute (NHLBI), the free repository will help researchers develop treatments—through stem cell research—for diseases that affect the lungs.

  1. See the article in Boston Magazine
  2. See the article in Bostonia!

CReM investigators successfully differentiate human iPS cells into megs and erythroid progenitors

October 31, 2013 Thursday

Researchers from Boston University School of Medicine (BUSM) and Boston Medical Center (BMC) have generated the first known disease-specific induced pluripotent stem cell (iPSC) lines from a patient with familial transthyretin amyloidosis (ATTR). The findings, which are reported in Stem Cell Reports, may lead to new treatments for genetic diseases such as familial amyloidosis. the researchers used the iPSC to generate liver cells that secrete the disease-specific mutant protein as well as cardiac and neuronal cells, the downstream target tissues of the disease. Upon exposure to the mutant protein, the heart and neuronal cells displayed signs of stress and an increased level of cell death as compared to those exposed to normal protein, thereby recreating essential aspects of the disease in vitro. Furthermore, small molecule stabilizers of the mutant protein that are being tested in clinical trials show efficacy in this model, validating this iPSC-based, patient-specific in vitro system as a platform for testing therapeutic strategies.

  1. Induced Pluripotent Stem Cell Modeling of Multisystemic, Hereditary Transthyretin Amyloidosis

CReM Investigators Publish Research into Differentiation Capacity of iPSC

May 2, 2011 Monday

The directed differentiation of iPS and ES cells into definitive endoderm (DE) would allow the derivation of otherwise inaccessible progenitors for endodermal tissues. However, a global comparison of the relative equivalency of DE derived from iPS and ES populations has not been performed. Recent reports of molecular differences between iPS and ES cells have raised uncertainty as to whether iPS cells could generate autologous endodermal lineages in vitro. Here, we show that both mouse iPS and parental ES cells exhibited highly similar in vitro capacity to undergo directed differentiation into DE progenitors. With few exceptions, both cell types displayed similar surges in gene expression of specific master transcriptional regulators and global transcriptomes that define the developmental milestones of DE differentiation. Microarray analysis showed considerable overlap between the genetic programs of DE derived from ES/iPS cells in vitro and authentic DE from mouse embryos in vivo. Intriguingly, iPS cells exhibited aberrant silencing of imprinted genes known to participate in endoderm differentiation, yet retained a robust ability to differentiate into DE. Our results show that, despite some molecular differences, iPS cells can be efficiently differentiated into DE precursors, reinforcing their potential for development of cell-based therapies for diseased endoderm-derived tissues.

  1. See the press release!
  2. See the original publication in the Journal of Clinical Investigation: “Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes.”
  3. CReM Directors Profiled in Bostonia

CReM Investigators publish humanized version of the novel Stem Cell Reprogramming Vector “STEMCCA”

October 26, 2010 Tuesday

The development of methods to achieve efficient reprogramming of human cells while avoiding the permanent presence of reprogramming transgenes represents a critical step toward the use of induced pluripotent stem cells (iPSC) for clinical purposes, such as disease modeling or reconstituting therapies. Although several methods exist for generating iPSC free of reprogramming transgenes from mouse cells or neonatal normal human tissues, a sufficiently efficient reprogramming system is still needed to achieve the widespread derivation of disease-specific iPSC from humans with inherited or degenerative diseases. Here, we report the use of a humanized version of a single lentiviral “stem cell cassette” vector to accomplish efficient reprogramming of normal or diseased skin fibroblasts obtained from humans of virtually any age. Simultaneous transfer of either three or four reprogramming factors into human target cells using this single vector allows derivation of human iPSC containing a single excisable viral integration that on removal generates human iPSC free of integrated transgenes. As a proof of principle, here we apply this strategy to generate >100 lung disease-specific iPSC lines from individuals with a variety of diseases affecting the epithelial, endothelial, or interstitial compartments of the lung, including cystic fibrosis, α-1 antitrypsin deficiency-related emphysema, scleroderma, and sickle-cell disease. Moreover, we demonstrate that human iPSC generated with this approach have the ability to robustly differentiate into definitive endoderm in vitro, the developmental precursor tissue of lung epithelia. Stem Cells 2010;28:1728–1740

  1. publication in Stem Cells

MGH and CReM investigators engineer bioartificial rat lung

July 13, 2010 Tuesday

Investigators used a mild detergent to remove resident cells from a harvested rat lung, leaving a white scaffold that was reseeded with endothelial and epithelial cells. This bioartificial lung was characterized in vitro and successfully transplanted into a rat.

  1. Read press releases at Boston.com
  2. Reuters
  3. PhysOrg.com

CReM Investigators publish novel approach to gene therapy for pulmonary emphysema

June 4, 2010 Friday

Directed gene transfer into specific cell lineages in vivo is an attractive approach for both modulating gene expression and correcting inherited mutations such as emphysema caused by human ?1 antitrypsin (hAAT) deficiency. However, somatic tissues are mainly comprised of heterogeneous, differentiated cell lineages that can be short lived and difficult to specifically transfect. Here, we describe an intratracheally instilled lentiviral system able to deliver genes selectively to as many as 70% of alveolar macrophages (AMs) in the mouse lung. Following a single in vivo lentiviral transduction, genetically tagged AMs persisted in lung alveoli and expressed transferred genes for the lifetime of the adult mouse. A prolonged macrophage lifespan, rather than precursor cell proliferation, accounted for the surprisingly sustained presence of transduced AMs. We utilized this long-lived population to achieve localized secretion of therapeutic levels of hAAT protein in lung epithelial lining fluid. In an established mouse model of emphysema, lentivirally delivered hAAT ameliorated the progression of emphysema, as evidenced by attenuation of increased lung compliance and alveolar size. After 24 weeks of sustained gene expression, no humoral or cellular immune responses to hAAT protein were detected. Our results challenge the dogma that AMs are short lived and suggest that these differentiated cells may be a possible target cell population for in vivo gene therapy applications, including the sustained correction of hAAT deficiency.

  1. Press releases can be found at U.S. News & World Report
  2. and Science Blog
  3. Journal of Clinical Investigation publication of the method.

ARRA stimulus grant from the NIH Awarded to CReM: RC2 ‘Grand Opportunities (GO)’ Grant to study iPS Cells

January 1, 2010 Friday

CReM researchers have been awarded an RC2 GO grant to derive differentiated endodermal and hematopoietic lineages from human iPS cells. The multicenter study, lead by Boston University Principal Investigators, Drs. Darrell Kotton and Gustavo Mostoslavsky, applies reprogramming technology to derive human iPS cells and then characterize their differentiated progeny using bioinformatics approaches.

  1. CReM researchers have been awarded an RC2 GO grant
  2. NIH press release.

On-line summaries of the latest publications this year from CReM investigators

  1. Induced Pluripotent Stem Cell Modeling of Multisystemic, Hereditary Transthyretin Amyloidosis. Leung A, Nah SK, Reid W, Ebata A, Koch CM, Monti S, Genereux JC, Wiseman RL, Wolozin B, Connors LH, Berk JL, Seldin DC, Mostoslavsky G, Kotton DN, Murphy GJ. Stem Cell Reports. 2013 Oct 31;1(5):451-463. PMID: 24286032 [PubMed - as supplied by publisher] Free PMC Article Related citations Select item 23723449
  2. The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation. Smith BW, Rozelle SS, Leung A, Ubellacker J, Parks A, Nah SK, French D, Gadue P, Monti S, Chui DH, Steinberg MH, Frelinger AL, Michelson AD, Theberge R, McComb ME, Costello CE, Kotton DN, Mostoslavsky G, Sherr DH, Murphy GJ. Blood. 2013 Jul 18;122(3):376-85. doi: 10.1182/blood-2012-11-466722. Epub 2013 May 30. PMID: 23723449 [PubMed - indexed for MEDLINE] Related citations Select item 23658981
  3. Lentiviral delivery of RNAi for in vivo lineage-specific modulation of gene expression in mouse lung macrophages. Wilson AA, Kwok LW, Porter EL, Payne JG, McElroy GS, Ohle SJ, Greenhill SR, Blahna MT, Yamamoto K, Jean JC, Mizgerd JP, Kotton DN. Mol Ther. 2013 Apr;21(4):825-33. doi: 10.1038/mt.2013.19. Epub 2013 Feb 12. PMID: 23403494 [PubMed - indexed for MEDLINE] Related citations
  4. Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Longmire TA, Ikonomou L, Hawkins F, Christodoulou C, Cao Y, Jean JC, Kwok LW, Mou H, Rajagopal J, Shen SS, Dowton AA, Serra M, Weiss DJ, Green MD, Snoeck HW, Ramirez MI, Kotton DN. Cell Stem Cell. 2012 Apr 6;10(4):398-411. doi: 10.1016/j.stem.2012.01.019. PMID: 22482505 [PubMed - indexed for MEDLINE] Free PMC Article Related citations
  5. Clonal genetic and hematopoietic heterogeneity among human-induced pluripotent stem cell lines. Mills JA, Wang K, Paluru P, Ying L, Lu L, Galvão AM, Xu D, Yao Y, Sullivan SK, Sullivan LM, Mac H, Omari A, Jean JC, Shen S, Gower A, Spira A, Mostoslavsky G, Kotton DN, French DL, Weiss MJ, Gadue P. Blood. 2013 Sep 19;122(12):2047-51. doi: 10.1182/blood-2013-02-484444. Epub 2013 Aug 12. PMID: 23940280 [PubMed - indexed for MEDLINE] Related citations Select item 23272148
  6. Residual expression of reprogramming factors affects the transcriptional program and epigenetic signatures of induced pluripotent stem cells. Sommer CA, Christodoulou C, Gianotti-Sommer A, Shen SS, Sailaja BS, Hezroni H, Spira A, Meshorer E, Kotton DN, Mostoslavsky G. PLoS One. 2012;7(12):e51711. doi: 10.1371/journal.pone.0051711. Epub 2012 Dec 14. PMID: 23272148 [PubMed - indexed for MEDLINE] Free PMC Article Related citations Select item 23103873
  7. Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. Lafaille FG, Pessach IM, Zhang SY, Ciancanelli MJ, Herman M, Abhyankar A, Ying SW, Keros S, Goldstein PA, Mostoslavsky G, Ordovas-Montanes J, Jouanguy E, Plancoulaine S, Tu E, Elkabetz Y, Al-Muhsen S, Tardieu M, Schlaeger TM, Daley GQ, Abel L, Casanova JL, Studer L, Notarangelo LD. Nature. 2012 Nov 29;491(7426):769-73. doi: 10.1038/nature11583. Epub 2012 Oct 28. PMID: 23103873 [PubMed - indexed for MEDLINE] Free PMC Article Related citations Select item 21537085
  8. Mouse ES and iPS cells can form similar definitive endoderm despite differences in imprinted genes. Christodoulou C, Longmire TA, Shen SS, Bourdon A, Sommer CA, Gadue P, Spira A, Gouon-Evans V, Murphy GJ, Mostoslavsky G, Kotton DN. J Clin Invest. 2011 Jun;121(6):2313-25. doi: 10.1172/JCI43853. Epub 2011 May 2. PMID: 21537085 [PubMed - indexed for MEDLINE] Free PMC Article Related citations
  9. Generation of human induced pluripotent stem cells from peripheral blood using the STEMCCA lentiviral vector. Gianotti-Sommer A, Rozelle SS, Sullivan S, Mills JA, Park SM, Smith BW, Iyer AM, French DL, Kotton DN, Gadue P, Murphy GJ, Mostoslavsky G. StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008-.
2013 Apr 29. PMID: 23658981 [PubMed] Books & Documents Related citations Select item 23149977 Next-generation regeneration: the hope and hype of lung stem cell research. Kotton DN. Am J Respir Crit Care Med. 2012 Jun 15;185(12):1255-60. doi: 10.1164/rccm.201202-0228PP. Epub 2012 Apr 19. Review. PMID: 22517787 [PubMed - indexed for MEDLINE] Related citations
  10. Generation of human induced pluripotent stem cells from peripheral blood using the STEMCCA lentiviral vector. Sommer AG, Rozelle SS, Sullivan S, Mills JA, Park SM, Smith BW, Iyer AM, French DL, Kotton DN, Gadue P, Murphy GJ, Mostoslavsky G. J Vis Exp. 2012 Oct 31;(68). doi:pii: 4327. 10.3791/4327. PMID: 23149977 [PubMed - indexed for MEDLINE] Free PMC Article Related citations
  11. Regeneration and orthotopic transplantation of a bioartificial lung. Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP. Nat Med. 2010 Aug;16(8):927-33. doi: 10.1038/nm.2193. Epub 2010 Jul 13. PMID: 20628374 [PubMed - indexed for MEDLINE] Related citations