Adipose-derived stem cells weigh in as novel therapeutics for acute lung injury

Acute lung injury is characterized by intense neutrophilic lung inflammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. There is an urgent need for effective therapies for acute lung injury. Zhang and colleagues tested the efficacy of adipose-derived stem cells in acute lung injury in mice. When adipose-derived stem cells were delivered to mice that had been challenged with lipopolysaccharide, they potently limited acute lung inflammation and injury in the mice, indicating that adipose-derived stem cells have therapeutic potential in acute lung injury in humans. Herein, we discuss the advantages and potential limitations of using adipose-derived stem cells as therapeutics for human acute lung injury.

MSCs include bone marrow-derived stem cells (BMSCs), MSCs in umbilical cord blood, and adipose-derived stem cells (ASCs). In the fi eld of ALI/ARDS cell-based therapeutics, most attention has focused on BMSCs, which have therapeutic effi cacy in rodent and human tissue models of ALI and sepsis [3,4]. However, a number of barriers that may limit the clinical usefulness of BMSCs in human ALI/ARDS have been identifi ed [5,6] ( Table 1). Like BMSCs, ASCs have anti-infl ammatory and immuno-suppressive activities. ASCs inhibit immune cell activation and proliferation by inducing cell-to-cell contact and signaling and releasing mediators that limit tissue injury [7]. ASCs have greater anti-infl ammatory potential than BMSCs because they secrete higher levels of bioactive mediators [8]. Th is and other properties of ASCs (Table 1) make them an attractive alternative to BMSCs as cell-based therapeutics for human ALI/ARDS. Consistent with this concept, recent studies have shown that transplantation of autologous ASCs attenuates ischemia-reperfusion lung injury in rodents [9,10].
Th e paper by Zhang and colleagues [11] builds upon this literature by examining whether ASCs have effi cacy in a model of direct ALI in mice. Zhang and coworkers challenged mice with bacterial lipopolysaccharide (LPS) by oropharyngeal route, and 4 h later ASCs isolated from syngeneic mice (mASCs) or humans (hASCs) were delivered to the mice by the same route, and ALI severity was assessed 24 and 72 h later. Th e LPS-challenged and mASC-or hASC-treated mice lost less body weight, and had decreased alveolar-capillary barrier injury as assessed by broncho-alveolar lavage fl uid albumin levels, and reduced alveolar septal thickening and exudates when compared with LPS-challenged mice not treated with ASCs. Treatment of the LPS-challenged mice with hASCs and mASCs also reduced polymorphonuclear neutro phil infl ux into the lungs, and suppressed lung levels of pro-infl ammatory mediators. Murine ASCs increased lung levels of anti-infl ammatory interleukin-10 in LPS-challenged mice.
A strength of the paper is its novel focus on ASCs as a therapy for ALI, and its approach to test ASCs therapeutically (rather than prophylactically) in an ALI model Abstract Acute lung injury is characterized by intense neutrophilic lung infl ammation and increased alveolar-capillary barrier permeability leading to severe hypoxemia, and is associated with high mortality despite improvements in supportive care. There is an urgent need for eff ective therapies for acute lung injury. Zhang and colleagues tested the effi cacy of adipose-derived stem cells in acute lung injury in mice. When adipose-derived stem cells were delivered to mice that had been challenged with lipopolysaccharide, they potently limited acute lung infl ammation and injury in the mice, indicating that adipose-derived stem cells have therapeutic potential in acute lung injury in humans. Herein, we discuss the advantages and potential limitations of using adiposederived stem cells as therapeutics for human acute lung injury. that induces robust neutrophilic lung infl ammation. Additionally, the authors compared the therapeutic effi cacy of human versus murine ASCs. While both hASCs and mASCs attenuated ALI, it is noteworthy that for most ALI parameters examined, mASCs were more potent than hASCs. However, it is possible that hASCs have greater potency at restraining acute lung infl ammation in human subjects.
Th e study of Zhang and colleagues has several limitations that need to be addressed before ASCs can be advanced to human clinical trials. First, no single ALI animal model can completely reproduce all the pathologic features of human ALI/ARDS. While the LPS model studied by Zhang and coworkers induces robust neutrophilic lung infl ammation, it causes only modest alveolar-capillary barrier injury, which is a hallmark of ALI/ARDS. Th us, it will be important to test the effi cacy of ASCs in ALI models associated with severe ALI (such as hyperoxia and acid-induced ALI) and to assess the eff ects of ASCs on physiologic readouts of ALI, including lung compliance and hypoxemia. Second, ALI/ARDS in humans is often initiated by bacterial infections, but the model chosen (LPS-mediated ALI) causes sterile lung infl ammation. Given that ASCs suppress immune responses, it will be important to assess their eff ects on host responses to pathogens that can cause ALI/ARDS. Th ird, the mechanisms by which ASCs produce their benefi cial eff ects in this model were not addressed. Fourth, given that ARDS patients are often not treated within the fi rst 4 hours of illness (the single time-point when ASCs were delivered to mice in this study), future studies should determine how late in the disease course ASCs can be delivered and still induce a protective eff ect and for how long this protective eff ect is sustained. Moreover, the long-term safety of delivering ASCs was also not assessed in this study. It is noteworthy in this respect that hASCs promote the growth of tumor cells [12]. Th erefore, before ASCs can be used to treat human subjects, it will be necessary to investigate their longterm safety in animals.

Conclusion
Th e study by Zhang and colleagues provides evidence that ASCs have potential as novel cell-based therapeutics for ALI/ARDS. Th e next logical step towards advancing ASCs into human clinical trials for ALI/ARDS will be to further test ASCs for their effi cacy and safety in additional small and large animal models of ALI, including models more clinically relevant than the LPSmediated ALI model studied by Zhang and colleagues.

ASCs BMSCs
Isolation of cells Safe, relatively non-invasive and inexpensive procedure. Adipose tissue is abundant, expendable, easily accessible, and can be a waste product of many therapeutic and cosmetic procedures