Lung-Derived Mesenchymal Stromal Cell Post-Transplantation Survival, Persistence, Paracrine Expression, and Repair of Elastase-Injured Lung

Abstract

While multipotent mesenchymal stromal cells have been recently isolated from adult lung (L-MSCs), there is very limited data on their biological properties and therapeutic potential in vivo. How L-MSCs compare with bone marrow-derived MSCs (BM-MSCs) is also unclear. In this study, we characterized L-MSC phenotype, clonogenicity, and differentiation potential, and compared L-MSCs to BM-MSCs in vivo survival, retention, paracrine gene expression, and repair or elastase injury after transplantation. L-MSCs were highly clonogenic, frequently expressed aldehyde dehydrogenase activity, and differentiated into osteocytes, chondrocytes, adipocytes, myofibroblasts, and smooth muscle cells. After intravenous injection (2 h), L-MSCs showed greater survival than BMMSCs; similarly, L-MSCs were significantly more resistant than BM-MSCs to anchorage independent culture (4 h) in vitro. Long after transplantation (4 or 32 days), a significantly higher number of CD45 neg L-MSCs were retained than BM-MSCs. By flow cytometry, L-MSCs expressed more intercellular adhesion molecule-1 (ICAM-1), platelet derived growth factor receptor alpha (PDGFRa), and integrin a2 than BM-MSCs; these proteins were found to modulate endothelial adherence, directional migration, and migration across Matrigel in L-MSCs. Further, L-MSCs with low ICAM-1 showed poorer lung retention and higher phagocytosis in vivo. Compared with BM-MSCs, L-MSCs expressed higher levels of several transcripts (e.g., Ccl2, Cxcl2, Cxcl10, IL-6, IL-11, Hgf, and Igf2) in vitro, although gene expression in vivo was increased by L-MSCs and BM-MSCs equivalently. Accordingly, both L-MSCs and BM-MSCs reduced elastase injury to the same extent. This study demonstrates that tissuespecific L-MSCs possess mechanisms that enhance their lung retention after intravenous transplantation, and produce substantial healing of elastase injury comparable to BM-MSCs.

Age Dependence of Lung Mesenchymal Stromal Cell Dynamics Following Pneumonectomy

“…high Epcam neg cells [11], explant outgrowth MSCs [36], adherent cells isolated from dissociated tissue [29,34], and side population cells [10]. Furthermore, several studies, including this current article, have characterized LMSC populations as having high levels of clonogenicity (CFU-Fs) [4,11,36].…”

Lung Extracellular Matrix and Fibroblast Function

“…Mesenchymal stromal cells (MSCs), resident within lung tissue, appear to represent a viable pool of progenitor cells (reviewed in Reference 37) and have been investigated in animal models of lung disease (38)(39)(40). These studies demonstrate the reparative potential of MSCs and have led to a wave of clinical trials of MSC therapy in patients with various lung disorders (e.g., ARDS, IPF, and COPD).…”

Coming to terms with tissue engineering and regenerative medicine in the lung

“…For example, MSCs derived from human adipose tissue and bone marrow on decellularized rat lungs express markers of pulmonary epithelial cells (117), although the source of the MSCs may play a role in their local behavior such as cell attachment, migration, and proliferation. MSCs within lungs have also been identified that have the ability to express markers of ATI and ATII cells (73,95,214). In this regard, a particularly relevant finding is that MSCs may be less finicky toward the scaffold milieu in terms of attachment (19,21,170,180,213,217).…”