*Innovations in Cell Research and Therapy*

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

expression of major histocompatibility antigens, permitting allogeneic therapy without need for immunosuppression, and no safety issues have been identified in hundreds of patients [101].

Two recent phase 1 dose-escalation safety of MSCs in patients with ARDS [102] and septic shock [103] raised no safety concerns adding a growing body of evidence that MSCs can be safety administered intravenously at several millions cells per kilogram to critically ill patients. Zheng et al. assigned 12 patients with moderate-to-severe ARDS to receive 1 million adipose-derived MSCs/kg or saline, reporting no adverse infusion-related events [104]. Nevertheless, the intravenous administration of high doses of MSCs may be associated with vascular thrombosis. Recently published trials of MSCs in ARDS and in sepsis and studies in progress are summarized in **Table 2**.

Larger phase 2 and phase 3 trials are required to define the adverse events related to cell therapy. These future studies should be designed considering the use of fresh versus cryopreserved cell product, the optimal dosing and route administration regimen, and which biologic and clinical outcomes should be assessed for insights into safety and efficacy. Central challenges in ensuring consistency in final product in the cell therapy field are the lack of consensus for *in vitro* potency assays to optimize donor selection, MSC tissue source, and optimal MSC culture condition. Without an accepted potency assay, the lack of a signal of biological effect in patients is difficult to interpret. One approach may be to measure paracrine factors such as angiopoietin-1 and KGF. Phase 2 trials should identify which biological markers are altered by cell-based therapy. However, the optimal approach for patient selection in sepsis and ARDS trials remains a challenge. ARDS and sepsis are clinical syndromes rather than a disease, with a lack of specificity of clinical criteria. Thirty-five percent of patients with ARDS have a hyperinflammatory phenotype, associated with a higher mortality and a different therapeutic response. Patients with a hyperinflammatory phenotype might be better candidates for therapy with MSCs [105, 106].

There is a growing evidence for the therapeutic effects of extracellular vesicles from MSCs, raising the possibility that cell-free therapy consisting of exosomes or microvesicles or MSC culture media might be produced and could be tested in patients with sepsis, ARDS, acute kidney injury, or traumatic brain injury. Several steps would be needed for this approach to become a reality, including optimization of purification methods for isolation of the required fractions of extracellular vesicles from MSCs accompanied by a comprehensive characterization of RNA, microRNA, lipids, and proteins in exosomes or microvesicles [50].

Although cell donors are extensively screened to rule out systemic illnesses, other donor-related variables, such as age, may be important. MSCs from aging (murine) donors demonstrated reduced efficacy [107]. Variations in production and cryopreservation methods may impact variability in the function of MSCs when tested in preclinical models or in patients for specific clinical disorders. Dimethyl sulfoxide and cell debris are removed by centrifugation after the cryopreserved MSCs have been thawed and cells are suspended in plasmalyte before intravenous administration in preclinical studies of lung injury. Current clinical studies are focused on a single dose of MSC administration via the less-invasive intravenous route with the START trial demonstrating safety for this approach [108].
