Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome

Abstract

Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC’s effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.

Editorial: Mesenchymal Stromal Cell Therapy for Regenerative Medicine

“…Mesenchymal stromal/stem cell (MSC) therapies are increasingly explored as novel regenerative and immunomodulatory approaches to treat or prevent diseases (Pittenger et al, 2019 ; Hmadcha et al, 2020 ; Moll et al, 2020b ; Ringdén et al, 2022 ). These cells exhibit potent paracrine properties that can modulate host immune responses, lower inflammation, and orchestrate endogenous tissue repair, at both the local and the systemic level through multiple pathways (Singer and Caplan, 2011 ; Doorn et al, 2012 ).…”

“…The goal of our Research Topic is to highlight the latest advances in applications of MSCs for the treatment of a variety of diseases and their modes of action (MoA). A better understanding of the mechanisms underlying the therapeutic effect of MSCs can provide crucial insight into innovative strategies to enhance their effectiveness in clinical application (Singer and Caplan, 2011 ; Doorn et al, 2012 ; Galipeau and Sensebe, 2018 ; Moll et al, 2019 , 2020b , 2022 ; Pittenger et al, 2019 ; Ringdén et al, 2022 ). The subjects covered within this Research Topic include: (a) Therapeutic application of MSCs for major clinical indications, (b) Cellular and molecular mechanisms underlying therapeutic effects of MSCs, and (c) Strategies for enhancement of the therapeutic effects of MSCs and their products.…”

“…Numerous studies have assessed MSC therapies for treating a wide array of pathologies owing to their potent immunomodulatory and regenerative properties (Kabat et al, 2020 ). Typical clinical indications for MSC therapy include musculoskeletal repair, neurological and cardiovascular pathologies (e.g., stroke), cancer treatment, hematological and auto- or allo-immune complications (e.g., graft-vs.-host disease, GvHD), and more recently also complications associated with coronavirus disease 2019 (COVID-19), such as acute respiratory distress syndrome (ARDS) and sepsis (Soria-Juan et al, 2019 ; Hmadcha et al, 2020 ; Ringdén et al, 2022 ).…”

“…Crippa et al from the “IRCCS San Raffaele” in Milano, Italy, elucidate the “ Role of ex vivo expanded MSCs in determining hematopoietic stem cell transplantation outcome .” The transplantation of hematopoietic stem and progenitor cells (HSPC/HSCT) is the only curative option available today for several hematological and non-hematological diseases. However, HSCT is associated with several early and late complications, such as low HSPC engraftment and impaired hematopoietic recovery, immune-mediated graft rejection, and GvHD in the case of allotransplantation (Ringdén et al, 2022 ). MSCs are a key structural and functional component of the hematopoietic bone marrow niche (Sacchetti et al, 2007 ) and the authors here summarize the intrinsic supportive role of MSCs in vivo and the adoptive transfer of ex vivo -expanded cells.…”

“…Due to the perivascular nature of MSCs surrounding and maintaining the integrity and function of blood vessels (Bianco et al, 2008 , 2013 ; Crisan et al, 2008 ), lung pathology, such as the rapidly progressing COVID-19 associated ARDS (Moll et al, 2020a ), but also the more chronic idiopathic pulmonary fibrosis (IPF) (Meltzer and Noble, 2008 ), are among frequently envisioned indications for MSC therapy (Ringdén et al, 2022 ). Kassem and Kamal from “The British University in Cairo,” Egypt, give an update on “ MSCs and their extracellular vesicles (EVs): a potential game changer for the COVID-19 crisis ,” to employ their immunomodulatory and regenerative properties for lung repair.…”