Mesenchymal stem cells used to treat Acute Respiratory Distress

Acute Respiratory Distress Syndrome (ARDS) describes a spectrum of increasingly severe acute respiratory failure events. ARDS results from multiple causes that include infections, trauma and major surgery. Clinically, ARDS is the leading cause of death and disability in the critically ill.

The characteristics of ARDS includes a somewhat sudden onset, severe oxygen depletion or hypoxia, stiff lungs that do not expand or contract properly, and the presence of an inflammation in the lungs that results in pulmonary swelling (edema; see Ware LB, Matthay MA. N Engl J Med. 2000, 342:1334–49.).  In the US, there are 200,000 new cases each year, and carries a mortality rate of 40%. This is a mortality rate that is comparable to that seen from HIV infections and breast cancer. The prognosis of ARDS survivors is also somewhat poor. ARDS sufferers can also find themselves fighting with cognitive impairment, depression and muscle weakness. Also ARDS can saddle patients with substantial financial burdens (see Herridge MS, et al. N Engl J Med. 2003, 348:683–93 & Hopkins RO, et al. Am J Respir Crit Care Med. 2005, 171:340–7).

Despite decades of research on ARDS, there are no therapies for it and management of the disease remains supportive.  But now stem cells called “mesenchymal stem cells” offer a potentially successful treatment of ARDS.  Mesenchymal stem cells (MSCs) are multipotent cells stem cells that are derived from adult tissues and capable of self-renewal and can differentiate into cartilage-making cells (chondrocytes), bone-making cells (osteocytes), and fat cells (adipocytes).  Friedenstein and colleagues were the first to isolate MSCs from rodent bone marrow in 1976 ()m the bone marrow in 1976 (see Friedenstein AJ, Gorskaja JF, Kulagina NN. Exp Hematol. 1976, 4:267–74).   Since  their discovery, MSCs have been isolated from many other tissues, including fat, muscle, dermis, placenta, umbilical cord, peripheral blood, liver, spleen, and lung.  The fact that MSCs come from adult tissue, are relatively easy to isolate, and are capable of robust growth in culture, males them attractive candidates for regenerative medicine (see Prockop DJ, et al. J Cell Mol Med. 2010, 14:2190–9).  Additionally, MSCs are usually tolerated by the immune system, which means that they can be transplanted from one individual to another.

Earlier studies provided data that suggested that MSCs actually might differentiate into lung epithelial cells and directly replace the damaged and destroyed lung cells. For example, Kotton et al. demonstrated that bone marrow-derived cells could engraft into pulmonary epithelia and acquire the specific characteristics typical to lung epithelial cells (Kotton DN, et al. Development. 2001, 128:5181–8).  Krause and colleagues showed that transplantation of a single bone marrow-derived blood-cell making (hematopoietic) stem cell could give rise to cells of different organs, including the lung, and demonstrated that up to 20% of lung alveolar cells were derived from this single bone marrow stem cell (Krause DS, et al. Cell. 2001, 105:369–77).  Finally, Suratt and co-workers examined female patients who had received bone marrow transplants from male donors, and found that significant numbers of male bone marrow stem cells, which were detected by the presence of the Y chromosome, had formed cells that engrafted in the lungs of the female patients (Suratt BT, et al. Am J Respir Crit Care Med. 2003, 168:318–2).  Unfortunately, more recent studies have clearly demonstrated that even though MSCs definitely reduce experimental lung injury, engraftment rates are low (see Mei SH, et al. PLoS Med. 2007, 4:e269; & Ortiz LA, et al. Proc Natl Acad Sci U S A. 2007, 104:11002–7). This suggests that direct engraftment of mesenchymal stem cells in the lung is unlikely to be of large therapeutic significance.

Several experiments have suggested many different mechanisms by which MSCs might help injured lungs.  First, MSCs seem to slow down the immune response to lung injury (see Gupta N, et al. J Immunol. 2007, 179:1855–63 & Mei SH, et al. Am J Respir Crit Care Med. 2010, 182:1047–57).  However, instead of acting like classic “anti-inflammatory” drugs might work, MSCs actually decrease host damage that arises from the inflammatory response, but also enhance host resistance to bacterial infections (sepsis).  MSCs decrease the expression of small molecules called “cytokines” that encourage inflammation (see Danchuk S, et al. Stem Cell Res Ther. 2011, 2).  Conversely, they also produce a host of anti-inflammatory molecule (e.g., interleukin 1 receptor antagonist, interleukin-10, and prostaglandin E2; see Németh K, et al. Nat Med. 2009, 15:42–9).  Because of these activities, MSCs reduced the recruitment of white blood cells to the lung during episodes of lung damage.  This is important because when white blood cells are recruited to a damaged area, they act as though they are ticked off and damaged not just the invading bacteria, but anything that stands in their and that includes innocent bystanders.  Thus by keeping ticked off white bloods away from lung tissue, the lung is spared extensive damage.

Secondly, MSCs seem to increase the immune response to sepsis, and reduce lung-damage-induced systemic sepsis.  Sepsis refers to the colonization of the bloodstream by infecting microorganisms.  Damage to the lung epithelium and provide a door from the air we breathe and the bacteria that contaminate it to our bloodstream.  MSCs mitigate lung damage, and therefore, reduce lung-induced sepsis,  MSCs secrete prostaglandin-E2, and this molecule stimulates resident white blood cells in the lung, known as “alveolar macrophages” to produce a molecule called “IL-10.”  IL-10 prevents potentially damaging activated white blood cells from being summoned to the lung (see Németh K, et al. Nat Med. 2009, 15:42–9).   Additionally, MSCs secrete anti-microbial peptides such as LL-37 and  tumour-necrosis-factor-alpha-induced-protein-6 that retard bacterial growth (Krasnodembskaya A, et al. Stem Cells. 2010, 28:2229–3).  When given to mice with lung damaged-induced sepsis, transplanted MSCs increased clearance of bacteria from the lung anf enhanced destruction of the bacteria by resident white blood cells (Mei SH,et al. Am J Respir Crit Care Med. 2010, 182:1047–57).

Thirdly, MSCs aid lung regeneration following injury.  They do this by secreting molecules that protect cells and promote cell survival (so-called “cytoprotective agents”).  MSCs also secrete “angiopoeitin” and “keratinocyte growth factor,” which restore the growth and health of the lung alveolar epithelial and endothelial permeability.  These molecules enhance lung healing in ARDS animals (see Lee JW,et al. Proc Natl Acad Sci U S A. 2009, 106:16357–6Mei SH, et al. PLoS Med. 2007, 4:e269 & Fang X, et al. J Biol Chem 2010. 285:26211–2). 

Clearly MSCs show a very diverse cadre of mechanisms that favorably modulate the immune response, which reduces inflammation and inflammation injury, without compromising the integrity of the immune response.  They also hasten healing of damaged lung tissue.  These features make MSCs attractive therapeutic candidates for ARDS.

Preclinical have proven extremely hopeful.  Human trials are currently in the planning and early stages.  It is not clear what the right dosages of MSCs might be or what is the best way to administer them (intravenous, intra-tracheal, or intra-peritoneal).  Another hurdle is that MSCs are a very heterogeneous population once they are isolated.  Which cells in this mixed population are them best for helping ARDS patients?  All these questions much be addressed before human trials can definitively test MSC treatments for ARDS.