Lee Lab

About

Welcome to the Lee Lab

For the past several years, my research has focused on the mechanisms by which mesenchymal stem cells (MSC) may normalize alveolar epithelial permeability and fluid transport in animal and human models of acute lung injury (ALI), including a novel ex vivo perfused human lung preparation injured by endotoxin or bacteria, in collaboration with Michael Matthay, MD.

More recently, my laboratory has begun studying the roles of microvesicles (MVs) released by both embryonic and adult stem cells in lung injury and cancer as a possible therapeutic and as an alternative to the stem cells themselves. MVs are circular membrane fragments (50-200 nM in size) released from endosomal compartment as exosomes or shed from the surface membranes, which retain the phenotype of the cells from which they originate. In various models of injury, MSC MVs, through surface receptors, homed to the site of inflammation and interacted with the injured epithelium or endothelium through transfer of mRNA, microRNA, protein, receptor and/or organelle.

Major Goals: To understand (1) the mechanisms how microvesicles are formed by stem cells, (2) how pre-conditioning the stem cells can change the phenotype of the released microvesicles and (3) whether the therapeutic potency of the microvesicles can be enhanced using various models of lung injury or cancer.

Funding Sources: NIH NHLBI, Hamilton Endowment Funds (UCSF Department of Anesthesiology), UCSF RAP Grant.

 

Leelab1.pngUnderlying Mechanisms of MSC Based Therapy for Acute Lung Injury. In acute lung injury, the therapeutic properties of MSC rely on both a paracrine mechanism and through interaction with other cells. Multiple mechanisms have been identified through which MSC therapy may repair the alveolar epithelium and endothelium during acute lung injury such as (1) secretion of paracrine soluble factors which restore alveolar fluid clearance, lung permeability and inhibit bacterial growth and (2) immunomodulation of innate and adaptive immune cells which reduce alveolar inflammation. Although not fully characterized, the potential of engraftment by in vivo modified MSC and the presence of endogenous adult stem cells with characteristics similar to MSC may also contribute to this therapeutic effect. (Figure made by Diana Lim. Published in Lee et al. Stem Cells 29(6): 913-919, 2011)

 

 

leelab2.pngPotential Mechanisms Underlying the Therapeutic Effect of Microvesicles Released by Mesenchymal Stem Cells. During acute lung injury, MSC MVs are targeted towards the injured alveolar epithelium by surface receptors, such as possibly CD44 or CD29 or through connexin 43 channels, leading to the endocytosis of its contents, which includes mRNA, miRNA, proteins and organelle. (Published in Zhu et al. Stem Cells 32(1):116-25, 2014)

 

 

 

 

Leelab3.pngElectron Microscopy Images of MVs Released by MSCs. Electron microscopy demonstrates that MVs are released by MSCs in vitro following stress such as serum starvation. MVs released into the inter-cellular gap separating two MSCs; bar is 2μm. Enclosed image shows purified MVs, which appears to be a collection of homogeneous spheroids; bar is 0.5μm. (Published in Zhu et al. Stem Cells 32(1):116-25, 2014

 

 

 

 

Leelab4.pngEffect of MSC MVs on Influx of Inflammatory Cells in Endotoxin-Induced ALI in Mice. The administration of MSC MVs reduced the influx of inflammatory cells in endotoxin-induced ALI in mice. IT MSC MVs improved lung injury as assessed by histology. H&E staining of lung sections at 48 h demonstrated a reduction in inflammatory cell influx, edema, blood and thickening of the interstitium in endotoxin-injured lungs treated with MSC MVs. The MVs derived from NHLF showed no therapeutic benefit on lung injury. Images are 10x magnification. (Published in Zhu et al. Stem Cells 32(1):116-25, 2014)

Research

Therapeutic use of microvesicles released by mesenchymal stem cells in bacterial pneumonia-induced acute lung injury, using both animal and human models.

Therapeutic use of conditioned medium or microvesicles released by mesenchymal stem cells in hypoxia/ischemia induced injury in a model of neonatal asphyxia.

Therapeutic use of microvesicles released by pre-conditioned mesenchymal stem cells in breast cancer with lung metastases.

 

Leelab1.pngUnderlying Mechanisms of MSC Based Therapy for Acute Lung Injury. In acute lung injury, the therapeutic properties of MSC rely on both a paracrine mechanism and through interaction with other cells. Multiple mechanisms have been identified through which MSC therapy may repair the alveolar epithelium and endothelium during acute lung injury such as (1) secretion of paracrine soluble factors which restore alveolar fluid clearance, lung permeability and inhibit bacterial growth and (2) immunomodulation of innate and adaptive immune cells which reduce alveolar inflammation. Although not fully characterized, the potential of engraftment by in vivo modified MSC and the presence of endogenous adult stem cells with characteristics similar to MSC may also contribute to this therapeutic effect. (Figure made by Diana Lim. Published in Lee et al. Stem Cells 29(6): 913-919, 2011)

 

 

leelab2.pngPotential Mechanisms Underlying the Therapeutic Effect of Microvesicles Released by Mesenchymal Stem Cells. During acute lung injury, MSC MVs are targeted towards the injured alveolar epithelium by surface receptors, such as possibly CD44 or CD29 or through connexin 43 channels, leading to the endocytosis of its contents, which includes mRNA, miRNA, proteins and organelle. (Published in Zhu et al. Stem Cells 32(1):116-25, 2014)

 

 

 

 

 

Leelab3.png

Electron Microscopy Images of MVs Released by MSCs. Electron microscopy demonstrates that MVs are released by MSCs in vitro following stress such as serum starvation. MVs released into the inter-cellular gap separating two MSCs; bar is 2μm. Enclosed image shows purified MVs, which appears to be a collection of homogeneous spheroids; bar is 0.5μm. (Published in Zhu et al. Stem Cells 32(1):116-25, 2014) 

 

 

 

Leelab4.pngEffect of MSC MVs on Influx of Inflammatory Cells in Endotoxin-Induced ALI in Mice. The administration of MSC MVs reduced the influx of inflammatory cells in endotoxin-induced ALI in mice. IT MSC MVs improved lung injury as assessed by histology. H&E staining of lung sections at 48 h demonstrated a reduction in inflammatory cell influx, edema, blood and thickening of the interstitium in endotoxin-injured lungs treated with MSC MVs. The MVs derived from NHLF showed no therapeutic benefit on lung injury. Images are 10x magnification. (Published in Zhu et al. Stem Cells 32(1):116-25, 2014)

Publications

Publications (2014-2016)

Manuscripts

  1. Zhu, YY, Feng, XM, Abbott, J, Fang, X, Hao, Q, Monsel, A, Qu, JM, Matthay, M, and Lee, JW. Human mesenchymal stem cell microvesicles for treatment of E.coli endotoxin induced acute lung injury in mice. Stem Cells 32(1):116-25, 2014. Article selected for F1000Prime.
  2. Ware, LB, Landeck, M, Koyama, T, Zhao, Z, Singer, J, Kern, R, Johnson, E, Janz, DR, Bernard, GR, Lee, JW, Matthay, MA,
and the California Transplant Donor Network. A Randomized Trial of Nebulized Albuterol to Enhance Resolution of Pulmonary Edema in 506 Brain Dead Organ Donors. Am J Transplant 14(3):621-8, 2014.
  3. McAuley, DF, Curley, GF, Hamid, UI, Laffey, JG, Abbott, A, McKenna, DH, Fang, X, Matthay, MA, and Lee, JW. Clinical Grade Allogeneic Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in part through a KGF-dependent mechanism in Human Lungs Rejected for Transplantation. Am J Physiol Lung Cell Mol Physiol 306(9):L809-15, 2014.  Article was selected for APSselect, an acknowledgement of the best of recent submissions to the American Physiological Society journals.
  4. Asmussen, S, Ito, H, Traber, DL, Lee, JW, Cox, RA, Hawkins, HK, McAuley, DF, McKenna, DH, Traber, LD, Zhou, H, Herndon, Wilson, J, DN, Prough, DS, Matthay, MA and Enkhbaatar, P. Human Mesenchymal Stem Cells Reduce The Severity of Acute Lung Injury in an Ovine Model of Bacterial Pneumonia and Sepsis. Thorax 69(9):819-25, 2014.
  5. Ware, LB, Lee, JW, Wickersham, N, Nguyen, J, Matthay, MA, Calfee, CS and the California Transplant Donor Network. Donor smoking is associated with increased pulmonary edema and biomarkers of inflammation and lung epithelial dysfunction in the ex vivo donor lung. Am J Transplant 14(10):2295-302, 2014.
  6. Mar, JS, Nagalingam, NA, Song, Y, Onizawa, M, Lee, JW, and Lynch, SV.  VSL#3 supplementation of mice is associated primarily with changes in ileal microbiota composition and amelioration of DSS-induced colitis.  Gut Microbes 5(4):494-503, 2014.
  7. Liu, KD, Wilson, JG, Zhuo, H, Caballero, L, McMillan, M, Fang, X, Cosgrove, K, Calfee, CS, Lee, JW, Kangelaris, K, Gotts, J, Rogers, A, Levitt, J, Wiener-Kronish, J, DeLucchi, K, Leavitt, A, McKenna, D, Thompson, BT, Matthay, MA.  Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem cells for the treatment of moderate-severe acute respiratory distress syndrome.  Annals of Intensive Care 4:22, 2014.
  8. Wilson, JG, Liu, KD, Zhuo, H, Caballero, L, McMillan, M, Fang, X, Cosgrove, K, Vojnik, R, Calfee, CS, Lee, JW, Rogers, AJ, Levitt, J, Wiener-Kronish, J, Bajwa, EK, Leavitt, A, McKenna, D, Thompson, BT, Matthay, MA. Mesenchymal Stem (Stromal) Cells for Treatment of ARDS: A Phase 1 Clinical Trial. Lancet Rep Med 3:24-32, 2015.
  9. Kropski, JA, Pritchett, JM, Zoz, DF, Crossno, PF, Markin, C, Garnett, ET, Degryse, Al, Mitchell, DB, Polosukhin, VV, Rickman, OB, Choi, L, Cheng, DS, McConaha, ME, Jones, BR, Gleaves, LA, Worrell, JA, Solus, JF, Ware, LA, Stein, CM, Lee, JW, Massion, PP, Zaynagetdinov, R, White, ES, Johnson, JE, Groshong, SD, Lancaster, LH, Young, LR, Steele, MP, Phillips III, JA, Cogan, JD, Loyd, JE, Lawson, LE, Blackwell, TS.  Extensive phenotyping of individuals at-risk for Familial Interstitial Pneumonia reveals clues to the pathogenesis of interstitial lung disease.  AJRCCM 191:417-26, 2015.
  10. Wei, H, Zeng, Q, Zhang, F, Xue, Q, Luo, Y, Lee, JW, Cao, X, Yu, B, Feng, X. Ghrelin inhibits proinflammatory responses and prevents cognitive impairment in septic rats.  Crit Care Med 43(5):e143-50, 2015.
  11. Gennai, S, Monsel, A, Hao, Q, Park, J, Matthay, MA, Lee, JW. Microvesicles Derived From Human Bone Marrow Mesenchymal Stem Cells Restored Alveolar Fluid Clearance in Marginal Donor Human Lungs Not Used For Clinical Transplantation. Am J Transplant  15(9):2404-12, 2015.
  12. Monsel, A, Zhu, YG, Gennai, S, Hao, Q, Hu, S, Rouby, JJ, Rosenzwajg, M, Matthay, MA, Lee, JW. Microvesicles Derived from Human Bone Marrow Mesenchymal Stem Cells Improve Survival in E.coli Pneumonia-induced Acute Lung Injury in Mice and Enhance Monocyte Phagocytosis of Bacteria. AJRCCM 192(3):324-36, 2015.
  13. Hao, Q, Zhu, YG, Monsel, A, Gennai, S, Lee, T, Xu, F, Lee, JW. Comparison of bone marrow and embryonic stem cell-derived human mesenchymal stem cells for treatment of E.coli Endotoxin-induced acute lung injury in mice. Stem Cells Transl Med 4(7):832-40, 2015.
  14. Prakash, A, Sundar, SV, Casbon , AJ, Zhu, YG, Tran, A, Lee, JW, Lowell, C, and Hellman, J.  Lung Ischemia Reperfusion (IR) is a Transient Sterile Inflammatory Process Influenced by Commensal Microbiota.  SHOCK 44(3):272-9, 2015.
  15. Fang, X, Abbott, J, Cheng, L, Colby, J, Lee, JW, Levy, B, Matthay, MA.  Mesenchymal Stem Cells Promote Resolution of Lung Injury by Lipoxin A4.  J Immunol 195(3):875-81, 2015.
  16. Rajasekaran, S, Tamatam, CR, Fang, J, Potteti, HR, Raman, V, Lee, JW, Matthay, MA, Mehta, D, Reddy, DM, and Reddy, SP.  Visualization of Fra-1/AP-1 activation during LPS-induced inflammatory lung injury using fluorescence optical imaging. Am J Physiol Lung Cell Mol Physiol 309(4):L414-24, 2015.
  17. Du, R, Richmond, B, Blackwell, ST, Cates, JM, Massion, PP, Ware, LB, Lee, JW, Kononov, AV, Lawson, WE, Blackwell, TS, Polosukhin, VV.  Secretory IgA From Tracheobronchial Submucosal Glands Does Not Compensate for its Surface Deficiency in Small Airways in Chronic Obstructive Pulmonary Disease. Virchows Archive 467(6):657-665, 2015.
  18. Chan, MCW, Kuok, DIT, Leung, CYH, Hui KPY, Valkenburg, SA, Lau, EHY, Nicholls, JM, Fang, X, Guan, Y, Lee, JW, Chan, RWY, Webster, RG, Matthay, MA, and Malik, JS.  Human mesenchymal stromal cells reverse influenza A H5N1 associated acute lung injury in vitro and in vivo. PNAS 113(13):3621-6, 2016.
  19. Gordon ED, Palandra J, Wesolowska-Andersen A, Ringel L, Rios CL, Lachowicz-Scroggins ME, Sharp LZ, Everman JL, MacLeod HJ, Lee JW, Mason RJ, Matthay MA, Sheldon RT, Peters MC, Nocka KH, Fahy JV, Seibold MA. IL1RL1 asthma risk variants regulate airway type 2 inflammation. JCI Insight. 2016 Sep 8; 1(14):e87871. PMID: 27699235
  20. Fernandez-Bustamante, A, Frendl, G, Sprung, J, Kor, D, Subramaniam, B, Martinez Ruiz, R, Lee, JW, Henderson, W, Moss, A, Mehdiratta, N, Colwell, MM, Bartels, K, Kolodzie, K, Vidal Melo, M; The Perioperative Research Network (PRN) investigators. Multicenter prospective evaluation of postoperative pulmonary complications in non-cardiothoracic surgical patients with severe systemic disease.  JAMA Surgery 2016 In Press.
  21. Liu, J, Kuwabara, A, Kamio, Y, Hu, S, Park, J, Hashimoto, T, Lee, JW.  Human mesenchymal stem cell-derived microvesicles prevent the rupture of intracranial aneurysm in part by suppression of mast cell activation via a PGE2-dependent mechanism.  Stem Cells 2016 In Press.

 

REVIEW ARTICLES/CHAPTERS/EDITORIALS: 

  1. Monsel, A, Zhu, YY, Hao, Q, Liu, J, Gennai, S, and Lee, JW.  Cell-based Therapy for Acute Organ Injury: Preclinical Evidence and On-going Clinical Trials Using Mesenchymal Stem Cells. Anesthesiology 121(5):1099-121, 2014.
  2. Gennai, S, Monsel, A, Hao, Q, Liu, J, Gudapati, V, and Lee, JW.  Cell-Based Therapy for Severe Traumatic Brain Injury.  British J Anesth 115 (2): 203–12, 2015.
  3. Lee, JW, Rocco, P, Pelosi, P.  Mesenchymal Stem Cell Therapy for Acute Respiratory Distress Syndrome: A Light at the End of the Tunnel?  Anesthesiology 122:238-40, 2015.  Editorial.
  4. Monsel, A, Zhu, YG, Gudapati, V, Lim, H, and Lee, JW.  Mesenchymal Stem Cell Derived Extracellular Vesicles for Acute Lung Injury.  Expert Opinion in Biological Therapy 16(7):859-71, 2016.
  5. Monsel, A, Zhu, YG, Gudapati, V, and Lee, JW.  Treatment of lung disease by MSC microvesicles (exosomes). Chapter in, The Biology and Therapeutic Application of Mesenchymal Cells. Ed. Kerry Atkinson. John Wiley Publishers Inc. Hoboken, New Jersey, USA. 2016.
  6. Matthay, M, Pati, S, and Lee, JW.   Therapeutic Role of Mesenchymal Stem Cells in Organ Injury.  Stem Cells 2016, In Press.
  7. Lee, JW.   Macrophage-derived microvesicles pathogenic role in acute lung injury.    Thorax, 2016.  Editorial.   In Press.
People

Jae-Woo Lee, MD 
Principle Investigator
Associate Professor of Anesthesiology, UCSF

Qi Hao, PhD 
Dr. Hao is studying the therapeutic use of microvesicles released by preconditioned mesenchymal stem cells to express pro-apoptotic agents for treatment of metastases from breast cancer in NOD/SCID mice in collaboration with Dr. Sam M. Janes (University College London, UK).

Antoine Monsel, MD 
Visiting Scholar
La Pitié-Salpétrière Hospital, Paris, France
Dr. Monsel is studying the therapeutic use of microvesicles released by preconditioned mesenchymal stem cells in small animal models of severe bacterial pneumonia.

Stephane Gennai, MD 
Visiting Scholar
Grenoble University Hospital, Grenoble, France
Using a novel ex vivo perfused human lung preparation, Dr. Gennai is studying the therapeutic use of microvesicles released by preconditioned mesenchymal stem cells in reconditioning human lungs declined for transplantation in collaboration with Dr. Michael A. Matthay (UCSF).

 

Contact

For individuals interested in post-doctoral positions, please contact:

Jae-Woo Lee, MD 
UCSF Medical Center
Department fo Anesthesiology
505 Parnassus Ave, Box 0648
leejw@anesthesia.ucsf.edu
Phone: (415) 476-0452