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Editorial Views  |   February 2015
Mesenchymal Stem Cell Therapy for Acute Respiratory Distress Syndrome: A Light at the End of the Tunnel?
Author Notes
  • From the Department of Anesthesiology, University of California San Francisco, San Francisco, California (J.-W.L.); Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil (P.R.M.R.); and Department of Surgical Sciences and Integrated Diagnostics, IRCCS San Martino IST, University of Genoa, Genoa, Italy (P.P.).
  • Corresponding article on page 363.
    Corresponding article on page 363.×
  • Accepted for publication October 11, 2014.
    Accepted for publication October 11, 2014.×
  • Address correspondence to Dr. Lee: leejw@anesthesia.ucsf.edu.
Article Information
Editorial Views / Critical Care / Respiratory System
Editorial Views   |   February 2015
Mesenchymal Stem Cell Therapy for Acute Respiratory Distress Syndrome: A Light at the End of the Tunnel?
Anesthesiology 2 2015, Vol.122, 238-240. doi:10.1097/ALN.0000000000000546
Anesthesiology 2 2015, Vol.122, 238-240. doi:10.1097/ALN.0000000000000546
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Image: ©Istock.
Image: ©Istock.
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ACUTE respiratory distress syndrome (ARDS) is a major cause of acute respiratory failure in critically ill patients. Despite improvements in understanding the pathophysiology of ARDS, its mortality remains high.1,2  Current treatments rely on supportive measures, such as lung-protective ventilation, conservative fluid management, and prone positioning.3–5  No pharmacological therapies from preclinical models have been translated to effective clinical treatment options. Mesenchymal stem or stromal cells (MSCs) may be an innovative therapy for ARDS. However, questions remain concerning the optimal dose, route, and timing of MSC administration after acute lung injury (ALI). In this issue of Anesthesiology, Hayes et al.6  address these concerns by studying the therapeutic characteristics of human bone marrow–derived MSCs in a validated animal model of ALI: ventilator-induced lung injury (VILI) in rats.
MSCs are adult, nonhematopoietic precursor cells derived from a variety of tissues (e.g., bone marrow, adipose tissue, and placenta) and have been used as therapy in multiple conditions (myocardial infarction and graft-versus-host disease). We, and other investigators, have reported that MSCs are effective in preclinical models of ALI due to their ability to secrete paracrine factors that regulate lung endothelial and epithelial permeability, including growth factors, anti-inflammatory cytokines, and antimicrobial peptides.7–10  These soluble factors can treat the major abnormalities underlying ALI, including impaired alveolar fluid clearance, altered lung permeability, dysregulated inflammation, and infection.
Based on promising preclinical data, two clinical trials are underway to test the safety and feasibility of using MSCs in ARDS. One (NCT01775774) is a multicenter study which will assess the safety of escalating intravenous doses (1–10 × 106 cells/kg) of allogeneic human bone marrow–derived MSCs in patients with moderate or severe ARDS. Another randomized, double-blind, placebo-controlled trial (NCT01902082) will assess safety and efficacy outcomes of allogeneic adipose-derived MSC therapy (1 × 106 cells/kg). However, questions remain as to the optimal dose and route of MSC delivery.
Optimal Dose and Route of MSC Delivery
Preclinical ALI studies have used mean MSC doses of 29.9 ± 20.4 × 106 cells/kg in mice and 20.3 ± 22.5 × 106 cells/kg in rats during the early phase of lung injury, suggesting that the effective dose is approximately 20–30 × 106 cells/kg.11  Most clinical trials using MSCs in lung disease, such as for idiopathic pulmonary fibrosis (NCT01385644) or bronchopulmonary dysplasia (NCT01632475), administered doses in the 1–20 × 106 cells/kg range, which appeared to be largely based on previous trials of MSCs in myocardial infarction, graft-versus-host disease, etc. To address this discrepancy between preclinical animal models and ongoing clinical trials, Curley et al.12  tested the efficacy of different doses of human MSCs (1–10 × 106 cells/kg) in the rat model of VILI. The authors found that intravenous administration of 10 × 106 MSCs/kg improved lung compliance, reduced alveolar edema/lung permeability, and helped restore lung architecture and oxygenation as compared with vehicle or fibroblasts.6  MSCs also decreased the influx of inflammatory cells into the injured alveolus, reducing expression of cytokine-induced neutrophil chemoattractant-1 and interleukin-6, while increasing the secretion of keratinocyte growth factor, which is known to enhance alveolar fluid clearance. More importantly, they found that MSC dose–response curve was not linear and the lowest effective dose of human MSCs, that is, the threshold above which greater efficacy was not seen, was 2 × 106 cells/kg. Therefore, MSC doses above this threshold provide no additional therapeutic benefits, but may increase the potential for complications. It is well known that, when administered intravenously, MSCs are initially trapped in the pulmonary circulation due to their size, which can precipitate embolic phenomena with increased right ventricular strain and elevated pulmonary artery pressures, complications that ARDS patients may not tolerate.
Most preclinical studies using endotoxin or bacterial pneumonia models of ALI administrated MSCs intratracheally, while those using bleomycin, ischemia/reperfusion, ventilator-induced, or other lung injury models delivered MSCs intravenously.11  To address the optimal route of MSC delivery, Hayes et al.6  compared the intravenous route to the intratracheal and intraperitoneal routes in VILI. They found that both intravenous and intratracheal MSC administration more effectively enhanced the recovery of arterial oxygenation and lung compliance, reduced lung permeability and influx of inflammatory cells into the injured alveolus, and restored lung structure compared to the intraperitoneal route. Although intrabronchial MSC instillation may not be optimal in hypoxemic ARDS patients, one Phase I clinical trial is underway to test the intratracheal administration of up to 20 × 106 cells/kg in neonates with severe bronchopulmonary dysplasia (NCT01632475). Additionally, for patients with pneumonia-associated ARDS, it is now known that MSCs possess direct antimicrobial activity through the secretion of antimicrobial peptides/proteins, such as cathelicidin-related antimicrobial peptides or lipocalin-2, as well as the ability to enhance macrophage/monocyte phagocytosis of bacteria. Thus, intrapulmonary delivery may ultimately be the most effective route to enhance bacterial clearance.13 
Timing of MSC Administration
Although preclinical animal models cannot replicate the natural course of ARDS, MSCs are usually given within 6 h of ALI, during the acute inflammatory phase.11  However, it is unlikely that any therapy for ARDS be administered so early in its course but once lung injury is firmly established.9  To address this issue, Hayes et al. administered MSCs at 0.25, 6, and 24 h after VILI, to coincide with both the acute inflammatory and the subsequent resolution phase of VILI. They found that MSCs significantly enhanced repair even when administered at 24 h after injury, suggesting the therapeutic effect was not solely anti-inflammatory.6 
Bone Marrow–derived Mononuclear Cells versus MSCs
To generate enough cells for administration, MSC preparations require in vitro culture expansion, which increases risks and entails several weeks of preparation. Therefore, most clinical trials have used human MSCs frozen in DMSO, which could negatively affect the therapeutic immunomodulatory effects of these cells.14  As an alternative, several investigators have focused on investigating the therapeutic potential of bone marrow–derived mononuclear cells (BMDMCs). Compared to MSC, the potential advantages of BMDMCs include autologous harvest on the day of administration, avoiding the need for an allogeneic source and lowering the cost in acute diseases such as ARDS; expression of genes involved in inflammatory response and chemotaxis by BMDMCs; and potential for crosstalk among multiple cell types in these preparations.15,16  In preclinical studies, BMDMCs from experimental donors with pulmonary and extrapulmonary ALI, although different in characteristics, were as effective as cells obtained from healthy donors in reducing inflammation and remodeling, suggesting a role for autologous BMDMC transplantation in clinical settings. BMDMC administration was also found to reduce lung inflammation and fibrosis regardless of the timing of injection after endotoxin-induced ALI.17–20 
Conclusion
Despite these advancements from preclinical studies, substantial challenges remain before MSC therapy can be used in clinical practice. As a relatively small number of patients with lung injury have received MSC therapy to date, further investigations are required to characterize its safety profile in terms of MSC quality control, bacteriological testing, viability, phenotype, and oncogenicity tests. The optimal timing and duration of administration, dose, source, delivery route, and schedule need to be evaluated. Finally, MSCs are produced by different companies; thus, regulations for their production require better definition because differences in cell production (e.g., passaging) may result in different effects. In conclusion, MSCs are potentially a very promising treatment for ARDS. Although it is difficult to extrapolate animal studies to bedside, the Hayes et al. study should help clinician scientists evaluate stem cell–based therapies for ARDS by defining the optimal dose, route, and timing of MSC administration.
Acknowledgments
Dr. Lee was funded by the National Heart, Lung, and Blood Institute (grant HL-113022) (Bethesda, Maryland). Dr. Rocco was funded by National Council for Scientific and Technological Development (Brasília, Brazil) and the Carlos Chagas Filho Rio de Janeiro State Research Supporting Foundation (Rio de Janeiro, Brazil).
Competing Interests
The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.
References
Rubenfeld, GD, Caldwell, E, Peabody, E, Weaver, J, Martin, DP, Neff, M, Stern, EJ, Hudson, LD Incidence and outcomes of acute lung injury.. N Engl J Med. (2005). 353 1685–93 [Article] [PubMed]
Ferguson, ND, Fan, E, Camporota, L, Antonelli, M, Anzueto, A, Beale, R, Brochard, L, Brower, R, Esteban, A, Gattinoni, L, Rhodes, A, Slutsky, AS, Vincent, JL, Rubenfeld, GD, Thompson, BT, Ranieri, VM The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material.. Intensive Care Med. (2012). 38 1573–82 [Article] [PubMed]
The Acute Respiratory Distress Syndrome Network:, Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.. N Engl J Med. (2000). 342 1301–8 [Article] [PubMed]
National Heart L, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann, HP, Wheeler, AP, Bernard, GR, Thompson, BT, Hayden, D, deBoisblanc, B, Connors, AF, Hite, RD, Harabin, AL National Heart L, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Comparison of two fluid-management strategies in acute lung injury.. N Engl J Med. (2006). 354 2564–75 [Article] [PubMed]
Guérin, C, Reignier, J, Richard, JC, Beuret, P, Gacouin, A, Boulain, T, Mercier, E, Badet, M, Mercat, A, Baudin, O, Clavel, M, Chatellier, D, Jaber, S, Rosselli, S, Mancebo, J, Sirodot, M, Hilbert, G, Bengler, C, Richecoeur, J, Gainnier, M, Bayle, F, Bourdin, G, Leray, V, Girard, R, Baboi, L, Ayzac, L PROSEVA Study Group, Prone positioning in severe acute respiratory distress syndrome.. N Engl J Med. (2013). 368 2159–68 [Article] [PubMed]
Hayes, M, Masterson, C, Devaney, J, Barry, F, Elliman, S, O’Brien, T, O’ Toole, D, Curley, GF, Laffey, JG Optimizing therapeutic potential of human mesenchymal stromal cells to enhance repair following ventilator induced lung injury in the rat.. Anesthesiology. (2015). 122 363–73
Németh, K, Leelahavanichkul, A, Yuen, PS, Mayer, B, Parmelee, A, Doi, K, Robey, PG, Leelahavanichkul, K, Koller, BH, Brown, JM, Hu, X, Jelinek, I, Star, RA, Mezey, E Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production.. Nat Med. (2009). 15 42–9 [Article] [PubMed]
Mei, SH, Haitsma, JJ, Dos Santos, CC, Deng, Y, Lai, PF, Slutsky, AS, Liles, WC, Stewart, DJ Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis.. Am J Respir Crit Care Med. (2010). 182 1047–57 [Article] [PubMed]
Maron-Gutierrez, T, Silva, JD, Asensi, KD, Bakker-Abreu, I, Shan, Y, Diaz, BL, Goldenberg, RC, Mei, SH, Stewart, DJ, Morales, MM, Rocco, PR, Dos Santos, CC Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice.. Crit Care Med. (2013). 41 e319–33 [Article] [PubMed]
Lee, JW, Krasnodembskaya, A, McKenna, DH, Song, Y, Abbott, J, Matthay, MA Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria.. Am J Respir Crit Care Med. (2013). 187 751–60 [Article] [PubMed]
Zhu, YG, Hao, Q, Monsel, A, Feng, XM, Lee, JW Adult stem cells for acute lung injury: Remaining questions and concerns.. Respirology. (2013). 18 744–56 [Article] [PubMed]
Curley, GF, Hayes, M, Ansari, B, Shaw, G, Ryan, A, Barry, F, O’Brien, T, O’Toole, D, Laffey, JG Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat.. Thorax. (2012). 67 496–501 [Article] [PubMed]
Gupta, N, Krasnodembskaya, A, Kapetanaki, M, Mouded, M, Tan, X, Serikov, V, Matthay, MA Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia.. Thorax. (2012). 67 533–9 [Article] [PubMed]
François, M, Copland, IB, Yuan, S, Romieu-Mourez, R, Waller, EK, Galipeau, J Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-γ licensing.. Cytotherapy. (2012). 14 147–52 [Article] [PubMed]
Maron-Gutierrez, T, Laffey, JG, Pelosi, P, Rocco, PR Cell-based therapies for the acute respiratory distress syndrome.. Curr Opin Crit Care. (2014). 20 122–31 [Article] [PubMed]
Antunes, MA, Laffey, JG, Pelosi, P, Rocco, PR Mesenchymal stem cell trials for pulmonary diseases.. J Cell Biochem. (2014). 115 1023–32 [Article] [PubMed]
Araújo, IM, Abreu, SC, Maron-Gutierrez, T, Cruz, F, Fujisaki, L, Carreira, HJr, Ornellas, F, Ornellas, D, Vieira-de-Abreu, A, Castro-Faria-Neto, HC, Muxfeldt Ab’Saber, A, Teodoro, WR, Diaz, BL, Peres Dacosta, C, Capelozzi, VL, Pelosi, P, Morales, MM, Rocco, PR Bone marrow-derived mononuclear cell therapy in experimental pulmonary and extrapulmonary acute lung injury.. Crit Care Med. (2010). 38 1733–41 [Article] [PubMed]
Prota, LF, Lassance, RM, Maron-Gutierrez, T, Castiglione, RC, Garcia, CS, Santana, MC, Souza-Menezes, J, Abreu, SC, Samoto, V, Santiago, MF, Capelozzi, VL, Takiya, CM, Rocco, PR, Morales, MM Bone marrow mononuclear cell therapy led to alveolar-capillary membrane repair, improving lung mechanics in endotoxin-induced acute lung injury.. Cell Transplant. (2010). 19 965–71 [Article] [PubMed]
Maron-Gutierrez, T, Silva, JD, Cruz, FF, Alegria, S, Xisto, DG, Assis, EF, Castro-Faria-Neto, HC, Dos Santos, CC, Morales, MM, Rocco, PR Insult-dependent effect of bone marrow cell therapy on inflammatory response in a murine model of extrapulmonary acute respiratory distress syndrome.. Stem Cell Res Ther. (2013). 4 123 [Article] [PubMed]
Silva, JD, Paredes, BD, Araújo, IM, Lopes-Pacheco, M, Oliveira, MV, Suhett, GD, Faccioli, LA, Assis, E, Castro-Faria-Neto, HC, Goldenberg, RC, Capelozzi, VL, Morales, MM, Pelosi, P, Xisto, DG, Rocco, PR Effects of bone marrow-derived mononuclear cells from healthy or acute respiratory distress syndrome donors on recipient lung-injured mice.. Crit Care Med. (2014). 42 e510–24 [Article] [PubMed]
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