Clinical development of MUSE cell treatment: The challenges

KEYWORDS:

• Cellular heterogeneity
• inflammation
• repair
• secretome
• tissue destruction

This article refers to:

The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation

In addition to haematopoietic stem cells contained in bone marrow (BM), the BM stroma contains rare cells of non-haematopoietic origin (representing 0.01–0.001% of total BM cells) capable of multi-lineage differentiation into fibroblasts, osteoblasts, adipocytes and chondrocyte progenitors. These non-haematopoietic BM-derived stromal cells support hematopoiesis and are variously known as mesenchymal stem cells, marrow stromal cells and more recently, mesenchymal stromal cells, all designated by the acronym MSC. In 2010 Prof Dezawa et al. from Tohoku University Medical Center in Sendai, Japan identified and characterized a subset of MSCs which showed pluripotent property and stemness, named multilineage-differentiating stress-enduring cells, MUSE cells.¹ However, in 2005 she already published in Science about a biological response of a crude MSC population which contained Pax7-positive cells that contributed to subsequent regeneration of muscle in degenerated muscles of rats.² Incubation of MSCs with bFGF generates MUSE cells and interestingly bFGF was an essential initial inducer of mucsle MSCs reported in the Science publication.

The ability of BM-derived MSC to suppress immune responses following hemopoietic bone marrow transplantation was initially shown in a case study of severe grade IV Graft versus Host Disease. Le Blanc et al. reported that repeated administration of purified haploidentical human BM-MSC following allogeneic stem cell transplantation completely reversed steroid-resistent GvHD.³ The results of this case study have been confirmed in a multicenter phase II trial for the treatment of severe acute GvHD, showing complete response in 30 of 55 patients treated with BM-MSC.⁴

Ever since this study other chronic diseases have been studied for responsiveness to allogeneic or autologous MSC treatment. Not only for the anti-inflammatory effects induced by these cells, but also for their ability to repair damaged tissue. In almost all small phase II clinical trials these responses were mixed. The discovery of MUSE cells and its effects in animal models of acute myocardial infarction or stroke in the brain support the clinical application of these cells with the aim to repair damaged tissue. In addition, application of MUSE cells in chronic diseases with tissue destruction such as in pulmonary emphysema and in survivors of adult respiratory distress syndrome is appealing.

The study reported by Alessio et al. contributes to the further understanding of mechanisms by which MSC's and MUSE cells act in an inflammatory milieu in which repair of a damaged organ is induced in order to restore its normal function.⁵ By using cells isolated from healthy donors, the authors investigated in a hypothesis free experiment the secretome of passage 2 to 3 of these cells. Interestingly, MUSE cells express more canonical protein pathways than MSC's and no canonical pathway could be exclusively assigned to MSC's only. Clearly, the authors identified in the MUSE cell secretome factors that play a key role in the regulation of stemness and immunomodulatory properties. Finally, they reported that the MUSE cell secretome contains proteins involved in anti-apoptotic activity, supporting the stress-enduring capacity of these cells.

The results reported by Alessio et al. originate from in vitro experiments. While aiming at the therapeutic application of MUSE cells in the clinical setting, it is important to understand if MUSE cells contain any or all of the behavioral variability reported for MSCs thusfar. Most likely, such studies do require the development of specific biomarkers. For example, not all inflammatory stimuli result in the same type and level of inflammatory mediators, and whereas some might lead to induction of anti-inflammatory MSCs, others might result in the generation of proinflammatory MSCs as reported by Waterman et al.⁶ This suggests an important role for the inflammatory environment in the host in determining response to MSC treatment, possibly also attributable to MUSE cell treatment. Furthermore, MSCs and MUSE cells isolated from different donors may exhibit different functional properties in spite of being culture-expanded under standardized culture conditions. Recent technical advances, such as cellular barcoding and index sorting may elucidate the heterogeneity of these cell preparations and allow the isolation of cell subsets with enhanced therapeutic efficacy.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.