Unraveling the Complexities of Mesenchymal Stromal Cell-based Therapies: One Size Doesn’t Fit All

Cell-based therapy utilizing mesenchymal stromal cells (MSCs) is an exciting and promising potential approach for lung diseases and critical illnesses. The rationale is based on a robust platform in which MSCs isolated from bone marrow, adipose, placental, and other tissues can, after either systemic or direct airway administration, ameliorate inflammation and injury in a wide range of preclinical disease models in both small and large animals (1, 2). Mechanistically, the MSCs are believed to exert protective and reparative effects through release of a range of paracrine mediators, including, but not limited to, antiinflammatory cytokines, growth factors, and extracellular vesicles (3). Other actions—for example, mitochondrial transfer—may also play a role (4).

This platform has led to a growing number of clinical investigations in a range of lung diseases and critical illnesses including both non–coronavirus disease (non–COVID-19) and COVID-19–associated acute respiratory distress syndrome and bronchopulmonary dysplasia (BPD) (5, 6). Although some trials have demonstrated benefit, not all have done so, and the ongoing challenge is to better devise optimal strategies for MSC use that incorporate a better mechanistic understanding of MSC actions in different diseases. Unresolved issues include source and optimal approaches for ex vivo expansion of the MSCs, dose, and dosing regimen. Of increasingly recognized importance, the patient inflammatory phenotype within any given disease entity also significantly affects MSC actions and, thus, potential therapeutic effects (7). The latter reflects the growing appreciation that the MSCs—by virtue of expressing cell surface damage and pathogen-associated molecular pattern receptors, such as the Toll-like receptors—respond to different inflammatory environments by altering their paracrine profile (8). The inflammatory environment also influences MSC clearance. Systemically administered MSCs lodge in the pulmonary capillary bed, where they are cleared over approximately 1–2 days through efferocytosis, apoptosis, and other host immune mechanisms (8). While lodged, they do not engraft but rather respond to the local inflammatory environment, with the resulting release of different profiles of paracrine mediators (9, 10). Some data also suggest that it is the host response to the MSCs that drives the observed beneficial effects rather than direct effects of the MSCs themselves (11, 12).

Another confounding factor is that MSCs isolated from any given tissue source themselves constitute a heterogenous population of cells with different attributes and potential therapeutic implications. This has confounded efforts to date to determine benchmarks for MSC “potency” for any given application. To this end, in this issue of the Journal, the study by Cyr-Depauw and colleagues (pp. 814–827) conducted at the Ottawa Hospital Research Institute provides important new information that helps to discriminate different populations utilizing as their model MSCs derived from umbilical cord blood samples from 5 healthy term donors (13). This is a leading group investigating potential MSC therapeutic approaches for BPD and other diseases. The underlying rationale was that single-cell transcriptomic profiling would identify different MSC populations with different protective and reparative effects. The investigators accordingly present robust data that discriminate the MSCs into two populations, one of which exhibited progenitor characteristics, enriched in genes with functions related to cell division, cell cycle, cell proliferation, DNA transcription, and chromatin organization. The other identified population was comprised of MSCs with fibroblast-like characteristics marked by high expression of genes related to extracellular matrix organization and collagen metabolism. It is interesting that four of the five donor samples exhibited the progenitor transcriptome, whereas the fifth was more fibroblastic. These observations correlate with some previously published data from other groups (14); however, the important step taken here was to then interrogate the different MSC populations in a preclinical rat model of BPD utilizing hyperoxia exposure. The investigators found that the MSCs with progenitor attributes were more protective than those with fibroblastic characteristics and further identified the differential expression of HLA-ABC between these groups as a discriminant that affected both MSC retention in the lung and protective effects. Differential expression of HLA gene expression and cell surface markers has also been observed in other studies in which human bone marrow–derived MSCs were exposed to clinical BAL samples from patients with acute respiratory distress syndrome versus lavage samples from healthy volunteers (15).

All told, the present study by Cyr-Depauw and colleagues provides further evidence that more mechanistic information is required for best clinical implementation of MSC-based cell therapies. In parallel, better understanding of cell therapy manufacturing to regulate production of MSCs with differing abilities is an area of active investigation. There are some limitations to the study, including that MSCs with progenitor attributes from only one of the four donors was assessed in the BPD model. These observations will need to be expanded in more wide-ranging studies. Nonetheless, the present data are an important advance in bringing MSC-based cell therapies to successful clinical use.