MSCs in treatment Interstitial Lung Disease in Children
Childhood interstitial lung disease (chILD) describes a group of respiratory diseases that can affect babies, children, and teens. It is also called diffuse lung disease [1]. Some children are born with an interstitial lung disease (ILD) while others develop an ILD later during childhood [2]. ChILD can be mild, serious, or life-threatening. Some types of chILD may get worse over time. The therapeutic strategy is mainly based on the use of corticosteroids, hydroxychloroquine, azithromycin, and supportive care; however, the efficacy is variable, and their long-term use is associated with severe toxicity [3]. In some special cases, some children do not respond to medication, which can cause symptoms to become more severe and require breathing support therapy. [3] Cell therapy now is a potential therapy in the treatment of interstitial lung disease in children, typically mesenchymal stem cells.
Researchers have proposed mesenchymal stem cells (MSCs) as a potential therapy to treat congenital lung diseases. Because of their tissue-regenerative, anti-fibrotic, and immunomodulatory properties, MSCs, either alone or in combination with other therapies, could be considered a new approach for repairing and regenerating the lung during disease progression and/or after post-surgical injury [4].
Childhood interstitial lung disease characteristics
Interstitial lung disease in children (chILD) is a group of highly heterogeneous and rare respiratory diseases with wide ranges in the age of onset and disease expression [5]. chILD causes inflammatory and fibrotic changes in the pulmonary parenchyma, resulting in gas exchange impairment and chronic respiratory failure. These conditions are associated with high morbidity and mortality [3]. Researchers have not yet fully explained the complex pathogenesis of chILD. The alveolar epithelium and abnormal mesenchymal activation may have a role, as suggested [2]. Researchers have suggested that the pathogenesis of chILD involves repeated injuries to vulnerable alveolar epithelial cells (AECs) and the inability of the alveoli to respond to these injuries, resulting in abnormal lung repair and progressive fibrosis [6].
chILD comprises over 200 different conditions, for which they have proposed different classification systems based on the etiology and physiopathology and lung biopsies [1,2]. Most times of chILD, there is no documented family history. Mutations in the surfactant protein (SP) genes, mainly in SP-B and -C genes, handle the familial form [3].
The clinical presentation of chILD varies, ranging from mild nonspecific symptoms to a very severe clinical picture. Usually, the earlier the disease onset, the more severe the presenting symptoms [7]. During the neonatal period, in term neonates, chILD may occur shortly after birth, with unexplained respiratory distress requiring intubation and ventilation [3]. During the first two years of life, common presentations include asymptomatic forms or nonspecific respiratory signs and symptoms, such as dyspnea, polypnea, dry cough, wheezing, recurrent respiratory infections, and exercise intolerance [8].
Older children can show tachypnoea, hyperoxia, digital clubbing, and/or cyanosis during exercise or at rest [8]. When clinically suspecting chILD, doctors use chest computed tomography (CT) scanning as the gold standard to evaluate the presence and extent of lung damage [9]. Within the diagnostic workup, doctors recommend blood tests, including genetic evaluation, immunological profile, and autoantibody studies, and they may consider environmental organic dust exposures [3].
The standard treatment of chILD is mainly supportive and based on oxygen supplementation, and/or ventilation, and respiratory physiotherapy [2]. Currently, when treating interstitial lung disease, medical facilities often apply anti-inflammatory and immunomodulating drugs such as corticosteroids, hydroxychloroquine and azithromycin depending on the severity [1]. Some new drugs, such as pirfenidone and nintedanib, may be new treatment options for children in the future. However, using these substances can cause toxic side effects or seriously damage other organs.
Mesenchymal stem cells (MSCs) and their potential in treating interstitial disease
Stem cell therapy represents a prospective approach in regenerative medicine for the repair, replacement, and rejuvenation of tissue [10]. In vitro, MSCs can self-renew and undergo expansion without compromising their potential for differentiation [11]. MSCs are multipotent cells that can differentiate into multiple tissue-forming cell lineages, such as osteoblasts, adipocytes, chondrocytes, tenocytes, and myocytes [3]. In addition, MSCs regulate immune and inflammatory responses. The lung originates from the endodermal and mesodermal germline. Each phase in lung development is reliant on inductive cues and reciprocal interactions between the pulmonary epithelium and the surrounding mesenchyme. [3] Loss of or abnormalities in cells and in their interactions can lead to severe anatomical and functional defects in the airway and alveoli [12]. MSCs are key cells in the connective pulmonary tissue hierarchy, supporting the crucial relationship between the epithelium and mesenchyme during branching morphogenesis [13]
[3] The need for research to advance the therapy of pulmonary diseases is mandatory to improve the prognosis and to prevent their progression in adulthood. A role for MSCs in therapy has been suggested in preclinical and clinical studies [3]. The therapeutic potential of MSCs is because of their paracrine effect, supported by their secretion of extracellular vesicles (EVs), transferring genetic material, and releasing of soluble factors such as cytokines. MSCs secrets the conditioned medium (CM) or secretome, which is defined as the products they release in their cultured medium [14].
In Vivo administration of MSCs, as well as of their products, appears a suitable approach for injured lung tissue repair by reducing fibrosis and stimulating proper alveolar and vascular repair [15]. It is a long-established fact that MSCs infuse intravenously; while circulating within the lungs, they remain partially entrapped, producing the pulmonary first-pass effect. MSCs therapy encounters this effect as a challenge when targeting other organs, but it can be an inherent advantage when directing biotherapy with MSCs to the lungs [16].
Both in vitro and in vivo, MSCs have been observed to differentiate into alveolar epithelial cells, showing their potential as a regenerative therapy for lung diseases [17]. Effectively, phase I clinical trials in patients with chronic obstructive pulmonary disease (COPD) confirmed the safety of MSCs; outcomes from phase I/II clinical trial administration and investigation showed their potential anti-inflammatory effects, reporting a reduction in C-reactive protein levels [18].
A systematic review and meta-analysis of preclinical studies, including different lung diseases such as bronchopulmonary dysplasia, asthma, pulmonary hypertension, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis, recorded comparable efficacy between CM and MSCs [19]. In line with these findings, in a mouse model of Escherichia coli endotoxin-induced model of acute lung injury (ALI), administration of MSC-derived CM induced a reduction in septal thickening, alveolar hemorrhage, alveolar infiltrates, and fibrin filaments compared to untreated mice. They observed similar reductions in neutrophils and lung permeability both after treatment with MSCs or CM [3]. In a rat model of bleomycin-induced pulmonary fibrosis, administration of MSC-derived CM reduced the deposition of collagen involved in fibrosis [19].
Recent evidence showed that MSCs offer a valid therapeutic approach for treating pediatric lung diseases, and researchers have evaluated the therapeutic effects of MSCs on respiratory diseases, which might serve as models for interstitial lung diseases [18]. They conducted a study to evaluate the safety and feasibility of treatment in preterm infants with disease enrolled in a previous trial [3]. Only one in nine children died six months after treatment, but it did not relate this adverse event to MSC transplantation. None of the remaining infants experienced treatment-related adverse events.
[20] Based on this evidence, in a clinical study performed by Pelizzo et al, the effects of repeated intravenous administration of allogeneic BM-MSCs were evaluated in a child with progressive obstructive pulmonary disease associated with an FLNA gene mutation. In this work, the researchers hospitalized a 32-day-old male child with respiratory distress and suspected congenital lung malformation. From healthy donor bone marrow, the researchers isolated and expanded ex vivo allogeneic BM-MSCs. The child received four infusions of MSCs (1× cells/kg) intravenously 4 weeks apart. Treatment with allogeneic MSCs improved the child’s respiratory condition. None of the remaining infants experienced treatment-related adverse events [20].
Therefore, the intravenous route, which takes advantage of the unique first-pass lung effect of MSCs, may be the optimal route of administration in the treatment of lung disease. In conclusion, this clinical study supports the use of MSCs in the treatment of interstitial lung disease in children.
Although these data encourage the use of MSCs as a potential therapy to treat interstitial lung disease. However, future research and clinical trials should evaluate side effects and improve procedures, and new methods have the potential to replace current clinical methods.
References:
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