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Collaborative Studies on Lung Stem Cell Biology and Cell Based Therapy
 
 


Marc B. Hershenson, M.D

University of Michigan Medical School

Dr. Marc Hershenson is the Frederick G.L. Huetwell Professor of Pediatrics and Communicable Diseases at the University of Michigan Medical School.  He is also Professor of Molecular and Integrative Physiology and Division Director of Pediatric Pulmonology. 

Dr. Hershenson received his medical degree from the University of Illinois.  He took his pediatrics residency at Children’s Memorial Hospital, Northwestern University Medical School, Chicago.  He received subspecialty training in pediatric critical care and pulmonology at The Children’s Hospital, Harvard Medical School, Boston.

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Consortium Research Title: Multipotent Lung Mesenchymal Cells in Neonatal Lung Injury

Consortium Research Description:

We have obtained pilot data demonstrating that tracheal aspirates from week-old premature infants undergoing mechanical ventilation for respiratory distress syndrome (RDS) contain colony-forming fibroblast- like cells with surface markers and differentiation potential typically found in mesenchymal stem cells. The cells are positive for Stro-1, CD73, CD90, CD105 and CD166, but negative for CD34, CD45 and CD11b, suggesting that they are of stromal but not hematopoietic origin. Further, they exhibit ample proliferative capacity and are capable of differentiation into osteocytes, adipocytes and myofibroblasts. Conditioned medium from these cells enhances epithelial growth and repair, inhibits squamous differentiation and contains basic fibroblast growth factor (bFGF/FGF-2), keratinocyte growth factor (KGF) and vascular endothelial cell growth factor (VEGF). Finally, the isolation of multipotent mesenchymal cells from the tracheal aspirates of premature infants with RDS is associated with a prolonged requirement for supplemental oxygen and the development of chronic lung disease, i.e., bronchopulmonary dysplasia (BPD). We therefore hypothesize that multipotent lung mesenchymal cells participate in neonatal lung repair and are a biomarker for lung injury. To test this general hypothesis, we propose the following Specific Aims.

Specific Aim 1: Determine mechanisms by which multipotent lung mesenchymal cells from premature infants are recruited to the airspaces. We hypothesize that epithelial injury induces expression of bFGF and monocyte chemoattractant protein (MCP)-1, thereby promoting lung mesenchymal cell migration to the airspaces.

Specific Aim 2: Characterize potential mechanisms by which multipotent lung mesenchymal cells participate in lung repair. We hypothesize that: 1) lung mesenchymal cells produce trophic factors capable of promoting respiratory epithelial repair; 2) when stimulated by transforming growth factor (TGF)-fl, lung mesenchymal cells differentiate into myofibroblasts, thereby promoting angiogenesis and fibrogenesis.

Specific Aim 3: Correlate the presence of multipotent lung mesenchymal cells in premature infants with the development and severity of chronic lung disease. We hypothesize that multipotent lung mesenchymal cells are biomarkers for lung injury and persistent pulmonary dysfunction. We will prospectively compare the clinical outcomes of premature infants from whom multipotent lung mesenchymal cells have been isolated with those from whom cells are not isolated, focusing on respiratory system compliance and days of oxygen supplementation.

Understanding the role of multipotent lung mesenchymal cells in the pathogenesis of BPD will lead to improvements in the treatment of this disease.

 

Hershenson Lab Information: 
University of Michigan Medical School
1150 West Medical Center Drive
Medical Sciences Research Building II, Room 3570B
Ann Arbor, MI 48109-5688
Phone: (734) 936-4200
Fax: (734) 764-3200

Administrative Assistant Contact Info:
Name: Karen Carskadon
Email Karen
Phone: (734) 936-4200

My laboratory studies cellular and molecular mechanisms underlying chronic airways diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and bronchopulmonary dysplasia. At this time, we are focusing on three main projects.

First, we are studying the mechanisms by which rhinovirus (RV), a common cold virus, induces exacerbations of asthma and COPD. We have found that binding and endocytosis of the virus is sufficient for airway epithelial cell cytokine expression, explaining how RV can induce exacerbations of asthma without substantial viral replication in the lower airways. On the other hand, viral replication is required for airway epithelial cell expression of interferons and interferon-dependent genes. We are currently examining the contributions of various pattern recognition receptors and cytoplasmic RNA helicases to this process. We are employing mouse models of RV infection, asthma and COPD in order to study these processes in vivo. Our latest results indicate that allergen sensitization and challenge alters the polarization and RV response of airway macrophages, leading to increased airway inflammation. Also, we have found using knockout mice that recognition of dsRNA by TLR3, while not required for viral clearance, initiates a pro-inflammatory signaling pathway leading to airways inflammation and hyperresponsiveness.

Second, we are studying the biochemical signaling mechanisms by which airway smooth muscle cells increase their size and contractile protein expression, processes which would be expected to increase airway narrowing in asthma. We have found that phosphorylation and inactivation of glycogen synthase kinase 3-beta increases cell size, contractile protein expression and cell shortening via both transcriptional and translational pathways. On the other hand, our recent results indicate that activation of p70 ribosomal S6 kinase increases cell size but not contractile protein expression or cell shortening. These data suggest that airway smooth muscle hypertrophy, without a selective increase in contractile protein expression, is insufficient for airway narrowing.

Third, we are studying fetal lung mesenchymal stromal cells found in the airways of premature infants with respiratory distress syndrome, and their potential role in lung injury and repair. Our studies indicate that these cells are capable of differentiating into either lipo- or myofibroblasts and likely originate in the lung, not bone marrow. Further, isolation of these cells from the tracheal aspirates of premature infants is associated with a greatly increased risk of bronchopulmonary dysplasia, a chronic lung disease. Future studies will attempt to examine the physiologic role of these cells in development and lung injury.

Recent Publications

  • Schneider D, Ganesan S, Comstock AT, Meldrum CA, Mahidhara R, Goldsmith AM, Curtis JL, Martinez FJ, Hershenson MB, Sajjan U.  Increased cytokine response of rhinovirus-infected airway epithelial cells in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2010 Apr 15. [Epub ahead of print] PMID: 20395558

  • Deng H, Hershenson MB, Lei J, Anyanwu AC, Pinsky DJ, Bentley JK. Pulmonary artery smooth muscle hypertrophy: Roles of glycogen synthase kinase-3beta and p70 ribosomal S6 kinase.  Am J Physiol Lung Cell Mol Physiol. 2010 Feb 26. PMID: 20190034

  • Popova AP, Bozyk PD, Goldsmith AM, Linn MJ, Lei J, Bentley JK, Hershenson MB.  Autocrine production of TGF-beta1 promotes myofibroblastic differentiation of neonatal lung mesenchymal stem cells.  Am J Physiol Lung Cell Mol Physiol. 2010 Feb 26. [Epub ahead of print]  PMID: 20190033

  • Wang Q, Nagarkar DR, Bowman ER, Schneider D, Gosangi B, Lei J, Zhao Y, McHenry CL, Burgens RV, Miller DJ, Sajjan U, Hershenson MB.  Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses. J Immunol. 2009 Dec 1; 183(11): 6989-97. Epub 2009 Nov 4.  PMID: 19890046

  • Nagarkar DR, Wang Q, Shim J, Zhao Y, Tsai WC, Lukacs NW, Sajjan U, Hershenson MB.
    CXCR2 is required for neutrophilic airway inflammation and hyperresponsiveness in a mouse model of human rhinovirus infection.  J Immunol. 2009 Nov 15;183(10):6698-707. Epub 2009 Oct 28.  PMID: 19864593
    Sajjan U, Ganesan S, Comstock AT, Shim J, Wang Q, Nagarkar DR, Zhao Y, Goldsmith AM, Sonstein J, Linn MJ, Curtis JL, Hershenson MB.  Elastase- and LPS-exposed mice display altered responses to rhinovirus infection.  Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L931-44. Epub 2009 Sep 11.  PMID: 19748999

  • Deng H, Hershenson MB, Lei J, Bitar KN, Fingar DC, Solway J, Bentley JK.  p70 ribosomal S6 kinase is required for airway smooth muscle cell size enlargement but not increased contractile protein expression.  Am J Respir Cell Mol Biol. 2009 Jul 31. [Epub ahead of print]
    PMID: 19648476

  • Bentley JK, Deng H, Linn MJ, Lei J, Dokshin GA, Fingar DC, Bitar KN, Henderson WR Jr, Hershenson MB.  Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3beta phosphorylation in a mouse model of asthma.  Am J Physiol Lung Cell Mol Physiol. 2009 Feb;296(2):L176-84. Epub 2008 Nov 14.  PMID:

  • Sajjan U, Wang Q, Zhao Y, Gruenert DC, Hershenson MB. Rhinovirus disrupts the barrier function of polarized airway epithelial cells.  Am J Respir Crit Care Med. 2008 Dec 15;178(12):1271-81. Epub 2008 Sep 11.  PMID: 18787220

  • Newcomb DC, Sajjan US, Nagarkar DR, Wang Q, Nanua S, Zhou Y, McHenry CL, Hennrick KT, Tsai WC, Bentley JK, Lukacs NW, Johnston SL, Hershenson MB.  Human rhinovirus 1B exposure induces phosphatidylinositol 3-kinase-dependent airway inflammation in mice.  Am J Respir Crit Care Med. 2008 May 15;177(10):1111-21. Epub 2008 Feb 14. PMID: 18276942

  • Deng H, Dokshin GA, Lei J, Goldsmith AM, Bitar KN, Fingar DC, Hershenson MB, Bentley JK.
    Inhibition of glycogen synthase kinase-3beta is sufficient for airway smooth muscle hypertrophy.
    J Biol Chem. 2008 Apr 11;283(15):10198-207. Epub 2008 Feb 5.  PMID: 18252708