Intravenous administration of adipose-derived stromal cells does not ameliorate bleomycin-induced lung injury in rats

Abstract

Background: Mesenchymal stromal cells (MSCs) have been studied intensively in regenerative medicine. Among MSCs, adipose tissue-derived stromal cells (ASCs) are relatively easy to obtain from a patient. Since ASCs are ideal candidates for use in the treatment of disease states including pulmonary fibrosis, we investigated whether intravenous injection of ASCs could exert a therapeutic effect against bleomycininduced lung injury in rats. Methods: Rats were intratracheally administered bleomycin, and one week later ASCs were isolated and cultured. Two weeks after bleomycin treatment ASCs or PBS (phosphate-buffered saline) were injected to the rats. Three or six weeks after bleomycin instillation, the total cell counts and their profile in bronchoalveolar lavage fluid (BALF) were measured, and a histological evaluation was semiquantitatively assessed for the injured lungs, followed by cell tracing. Results: The BALF cell counts and its profiles were not significantly different in the ASCs and PBS groups. Furthermore, ASC treatment led to no significant histological effect compared with the PBS treatment. Using a fluorescent cell tracer, it was noted that the ASCs homed to the injured lung areas, but some ASCs accumulated around scars, and scarcely migrated into the fibrotic areas. Conclusions: In the present study, the intravenous administration of ASCs could not reduce the severity of bleomycin-induced lung injury in a rat model. Although the ASC counts and passage numbers were suitable, the older age and fibrotic disease stage of the rats were likely responsible for the treatment failure.

Human Adipose-derived Mesenchymal Stem Cells Attenuate Early Stage of Bleomycin Induced Pulmonary Fibrosis: Comparison with Pirfenidone

“…In the present study, we have shown than AD-MSCs are efficacious in ameliorating the symptoms of pulmonary fibrosis by increasing survivability and protection from lung fibrosis comparatively better than pirfenidone. Earlier two studies also showed that AD-MSCs relived IPF and provide significant contribution to lung repair at an early stage of disease (16, 18), however, one study did not show any beneficial effect of intra-venous infusion of AD-MSCs either at 0 day or 14 day post bleomycin challenge in lung repair (27). Many studies have reported beneficial effects from MSCs derived from bone marrow, umbilical cord, and amniotic fluid for bleomycin induced lung injury in mice or rat model (28–30).…”

“…There is no available data suggesting that MSC administration once fibrosis is established will decrease fibrosis, rather several studies suggested that MSCs administration at the fibrotic lungs may not be effective, rather may increase lung fibrosis (27, 38, 39). Our attempt to infuse AD-MSC at fibrotic stage on day 14, 17 and 20 post bleomycin did not yield any results since most of the animals did not survive (data not shown).…”

“…These results were almost indistinguishable when compared with early treatment (11). These failures may be due to failure of sufficient migration of MSCs into the fibrotic area in order to inhibit increasing interstitial fibrosis when they were administered two to three weeks after bleomycin instillation (27). The timing of cell transplantation may therefore be a key determinant of the fate and function of stem cell, since cell survival and migration depended on the time of transplantation relative to injury.…”

A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis

“…In our study, ADSCs-SVF, were neither cultured nor expanded and were directly infused within the patients’ lungs after implementing a two-step activation procedure using a cocktail of autologous growth factors (PRP) [50] and photobiostimulation [51], two novel approaches known to amplify paracrine beneficial effects of MSCs. Furthermore, recent preclinical and human studies have raised significant concerns with regards to possible dysfunctional migratory and paracrine properties of ADSCs-SVF derived from older individuals [60] and mice [61]. In particular, Uji et al [61] recently reported that stromal cells derived from the adipose tissue of relatively older mice exhibited reduced migratory capacity and failed to attenuate bleomycin-induced lung fibrosis.…”

“…Furthermore, recent preclinical and human studies have raised significant concerns with regards to possible dysfunctional migratory and paracrine properties of ADSCs-SVF derived from older individuals [60] and mice [61]. In particular, Uji et al [61] recently reported that stromal cells derived from the adipose tissue of relatively older mice exhibited reduced migratory capacity and failed to attenuate bleomycin-induced lung fibrosis. While the subject of an ongoing study, cultures of ADSCs-SVF derived from representative patients with IPF revealed a significant increase in the number of ADSCs-SVF colonies and an overexpression of anti-inflammatory (IL1-receptor antagonist) and angiogenic (vascular endothelial growth factor-VEGF) mediators, following activation with PRP and laser irradiation.…”