Mesenchymal stromal cells (MSCs) have been primarily used in regenerative medicine as a cell-based therapy due to their unique capacity for multilineage differentiation, thus clinical research to date has focused on their regenerative effects. However, for researchers aiming to treat systemic autoimmune rheumatic diseases (SARDs), the most critical characteristic of MSCs is their ability to secrete immunomodulatory factors that regulate immune responses. MSCs exert their effects through both paracrine/endocrine secreted factors and direct cell-cell contact, influencing immune cells and local tissue within their microenvironment [1]. MSCs are chemotactically attracted to the sites of injury or inflammation – and in the context of systemic inflammation, this may involve widespread distribution throughout the body. MSCs mechanism of action has been extensively studied in preclinical animal models of systemic diseases. These studies have provided compelling evidence that MSCs can modulate multiple immune cell types simultaneously. MSCs are considered among the most promising cell therapies for autoimmune diseases, where broad and simultaneous immune cell activation is a hallmark of disease (Fig. 1A and B). Additionally, MSCs do not express major histocompatibility complex II (MHC-II] or costimulatory molecules [2,3]. This immunologic “privilege” helps prevent rejection reactions and cytokine release syndromes, making MSCs a safe and scalable option for clinical use in immune-mediated conditions.

The first clinical trial using MSCs was conducted in 1995 by Lazarus et al. [4] for patients with GVHD. Since then, MSCs have been used in numerous clinical trials worldwide. Despite decades of intensive research and more than 200 publications, the first FDA approval forMSC therapy (Ryoncel) specifically for steroid resistant graft-versus-host disease (GVHD) was just granted recently in December 2024. The slow pace of clinical translation has largely been attributed to the heterogeneous efficacy profiles of MSCs. Cells derived from different tissue sources such as adipose tissue, bone marrow, umbilical cord, peripheral blood, and even organ-derived MSCs like those from the kidney – exhibit distinct functional properties, which contribute to inconsistent outcomes across studies. Historically, most clinical trials have used bone marrow derived (BM-) MSCs, due to the extensive body of early research in regenerative medicine that established a foundation of safety and preliminary efficacy. However, even bone-marrow-derived MSCs display variability in therapeutic effectiveness between donors, further complicating clinical outcomes. This variability in MSC performance is thought to be a major factor contributing to the mixed or inconclusive results in many clinical trials. In response, the past decade has seen growing efforts to precondition or engineer MSCs to enhance their therapeutic potency and consistency, thereby improving their translational potential in clinical medicine.