**2.2 Induced pluripotent stem cells (iPSC)**

A new type of pluripotent cells, iPSCs, can be obtained by reprogramming animal and human somatic (differentiated) cells. Usually, iPSCs are obtained from dermal fibroblasts because it is an easy source and did not produce any damage to the donor when we obtain them. The cells should be dedifferentiated following


### **Table 1.**

*Summary of the cell sources and their benefits.*

reprogramming and finally are able to express four transcription factors such as Ocet3/4, Sox2, Klf-4, and c-Myc. They grow indefinitely and differentiate into all cell types of the human body, and also they can be obtained in autologous way reducing the graft-versus-host disease [20–22].

The main problem is that the dedifferentiation and reprogramming have low efficiency, and their genomic modification could create associated problems that until now are unknown or have not been studied and have a high tumorigenicity risk [23–25]. The potential applications of iPSCs in sepsis and ARDS are many [26, 27].

### **2.3 Endothelial progenitor cells (EnPC)**

The endothelial damage is one of the main hallmarks of ARDS, and EnPCs have the ability to regenerate endothelial cells and could have an unlimited role in repairing the damaged endothelium. EnPCs have been defined as circulating cells that have ability to adhere to the endothelium at sites of hypoxia and ischemia secreting pro-angiogenic factors and generate a new vessel [28].

EnPCs express hematopoietic surface cell markers such as CD34. However, the role, isolation, and identification of these cells are not completely elucidated.

EnPCs can be useful as a regenerative instrument to treat several vascular diseases, but the ability to adhere to the endothelium at sites of hypoxia and ischemia secretes pro-angiogenic factors and generates a new vessel [29, 30].

Very few pre-clinical studies have been published, which have used EnPCs in sepsis and ARDS [31–34].

## **2.4 Epithelial progenitor cells (EpPC)**

Some epithelial progenitors of the lung alveolar compartment have also been identified, but their isolation is really difficult and the number of cells that could be obtained is really low. EpPCs might be useful in the treatment of ARDS.

EpPCs are specified during development in each tissue and are highly regulated by epithelial-mesenchymal interactions. Different tissues have different EpPCs with small adjustments in their function; however, their maintenance, activation, and differentiation are regulated by the same pathways between all the tissues [35, 36].

The use of alveolar-epithelial type II cells (AE2C) for the treatment of ARDS has been demonstrated; these cells are more differentiated than EpPCs, but still can proliferate and differentiate into alveolar-epithelial type I cell, that are the complete differentiated cells in the lung epithelia. AE2C cells can only be isolated from the lungs of organ donors and may have problems in graft-versus-host disease [37–39]. The isolation of AE2C is laborious, but they have less ethical problems and tumorigenicity potential.

### **2.5 Mesenchymal stem cells (MSC)**

MSCs are the best described cells and mostly used as a cell therapy. MSCs are multipotent cells that have been isolated from several tissues such as umbilical cord blood, placenta, adipose tissue, lung, and bone marrow.

The International Society of Cellular Therapy defined that MSCs should follow the three criteria: (1) MSCs must be adherent to plastic; (2) MSCs must express some cell surface markers, such as CD105, CD90, and CD73, but must not express other markers, including CD45, CD34, CD14, or CD11b; and (3) MSCs must have the capacity to differentiate into mesenchymal lineages (osteoblasts, adipocytes, and chondroblasts) in *in vitro* conditions [40].

**7**

*Current Status of Stem Cell Therapy for Sepsis and Acute Respiratory Distress Syndrome*

but do not express major histocompatibility class II [42–44].

MSCs have a high degree of plasticity and can be differentiated into a variety of cell lineages, but they do not possess the complete plasticity of ESCs. However, MSCs have some advantages because of their easy isolation and enormous propagation in culture and also because their use does not involve the ethical problems associated to the use of ESCs [41]. Moreover, they can be obtained in autologous way diminishing the immune rejection problem. In addition, MSCs are not immunogenic; they have an innate ability to avoid detection by a recipient's immune system because they express intermediate levels of major histocompatibility class I

Several experimental studies have indicated that MSCs may have potential therapeutic application in sepsis and ARDS [45–49]. It has also been reported that MSCs release several microvesicles that might have the therapeutic potential [50, 51].

**3. Mesenchymal stem cell therapy for sepsis and acute respiratory** 

The complex pathophysiology of sepsis and also of ARDS requires a therapy with a wide range of properties. The heterogeneity of the host response in front of sepsis or ARDS makes it difficult to find a proper drug that works as a therapy. Stem cells are potential therapeutic agents with a diverse spectrum of action and can act at different levels of the pathophysiology of ARDS or sepsis, non only treating inflammation, moreover affecting coagulation, enhancing antimicrobial effect, modulating the innate and adaptive immune response, and reducing endothelium

MSCs can be administered intravenously, but then only a small percentage of injected cells arrive to the injury site. Usually, MSCs get trapped into the lung's microvasculature, and after some hours, they are engulfed by macrophages and they disappear. It is well known that cells do not engraft into the tissue and their primary action mechanism is the secretion of soluble factors with therapeutic properties. MSCs release into the extracellular media bioactive cytokines, chemokines, angiogenic factors, and/or growth factors. Moreover, it has been described that MSCs also release extracellular vesicles with bioactive compounds. Extracellular vesicles are small vesicles made by a phospholipid bilayer and encapsulate proteins, lipids, or miRNAs or other compounds that are protected from the media and can be phagocytosed by other cells and act on them. Nowadays, the use of extracellular vesicles to target specific cells is also a raising up therapy competing with cell therapies; however, there is still a lot to define about the secretome of the MSC to be able to mimic its

All these factors directly secreted to the media or inside extracellular vesicles regulate intracellular pathways from different cells and can act on the innate and adaptive immune system. The different effects or mechanisms are described in the

Inflammation is one of the main drivers of ARDS and sepsis pathogenesis. During ARDS, the injury of the lung endothelium and epithelium is producing a recruitment of pro-inflammatory cells such as neutrophils and monocytes into the alveolar space. These pro-inflammatory cells release several pro-inflammatory cytokines, for example, TNF-α, IL-1β, and IL-6 [52–54]. Moreover, neutrophils are secreting several ROS enhancing the damage of the endothelium and epithelial

*DOI: http://dx.doi.org/10.5772/intechopen.86108*

**distress syndrome**

permeability and edema.

therapeutic effects.

following sections and in **Figure 1**.

**3.1 Effects on the innate immune system**

layers propagating the damage [55–57].

### *Current Status of Stem Cell Therapy for Sepsis and Acute Respiratory Distress Syndrome DOI: http://dx.doi.org/10.5772/intechopen.86108*

MSCs have a high degree of plasticity and can be differentiated into a variety of cell lineages, but they do not possess the complete plasticity of ESCs. However, MSCs have some advantages because of their easy isolation and enormous propagation in culture and also because their use does not involve the ethical problems associated to the use of ESCs [41]. Moreover, they can be obtained in autologous way diminishing the immune rejection problem. In addition, MSCs are not immunogenic; they have an innate ability to avoid detection by a recipient's immune system because they express intermediate levels of major histocompatibility class I but do not express major histocompatibility class II [42–44].

Several experimental studies have indicated that MSCs may have potential therapeutic application in sepsis and ARDS [45–49]. It has also been reported that MSCs release several microvesicles that might have the therapeutic potential [50, 51].
