Mesenchymal Stem Cells in Immune-Mediated Bone Marrow Failure Syndromes

Abstract

Immune-mediated bone marrow failure syndromes (BMFS) are characterized by ineffective marrow haemopoiesis and subsequent peripheral cytopenias. Ineffective haemopoiesis is the result of a complex marrow deregulation including genetic, epigenetic, and immune-mediated alterations in haemopoietic stem/progenitor cells, as well as abnormal haemopoietic-to-stromal cell interactions, with abnormal release of haemopoietic growth factors, chemokines, and inhibitors. Mesenchymal stem/stromal cells (MSCs) and their progeny (i.e., osteoblasts, adipocytes, and reticular cells) are considered as key cellular components of the bone marrow haemopoietic niche. MSCs may interfere with haemopoietic as well as immune regulation. Evidence suggests that bone marrow MSCs may be involved in immune-mediated BMFS underlying pathophysiology, harboring either native abnormalities and/or secondary defects, caused by exposure to activated marrow components. This review summarizes previous as well as more recent information related to the biologic/functional characteristics of bone marrow MSCs in myelodysplastic syndromes, acquired aplastic anemia, and chronic idiopathic neutropenia.

Normal and Leukemic Stem Cell Niches: Insights and Therapeutic Opportunities

“…These data suggest that stromal genetic changes known to drive myeloid disorders in mice are also found in human tissues, and could similarly contribute to disease development. Other correlative and still controversial evidence includes the fact that stromal cell populations isolated from individuals with myeloid malignancies can carry genetic abnormalities that are different from the driver mutation(s) in the leukemic clone (Blau et al, 2007; Kastrinaki et al, 2013). One important caveat with these studies is that they were performed with serially expanded cells, which could therefore have acquired new genetic abnormalities as the direct consequence of the ex vivo culture.…”

“…In PMF, the degree of collagen fiber deposition and ECM remodeling is also directly correlated with overall patient survival (Pereira et al, 1990). In MDS, patient-derived stromal cells appear qualitatively different in their ability to support blast cell colonies and impaired in their ability to maintain long-term cultures of CD34 + HSPCs (Gidali et al, 1996; Aizawa et al, 1999), although these results are still somewhat controversial (Kastrinaki et al, 2013). Reduced contact inhibition in vitro , impaired ability to maintain hematopoietic differentiation and increased osteoblastic lineage gene expression are also aberrant features of stromal cells derived from pediatric MDS patients (Borojevic et al, 2004).…”

Soluble Factors on Stage to Direct Mesenchymal Stem Cells Fate

“…MSCs play an important role in maintaining and restoring hematopoiesis, thanks to the secretion of regulatory factors for HSC functionality (Kastrinaki et al, 2013). Scanty data are available the other way round.…”

De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes

“…It is rational to assume that MSC, derived from patients with hematological malignancies, harbor some partial defects, either primary or secondary, due to their exposure to altered marrow components. Extensive data have already shown interactions between leukemic cells and their microenvironment, supporting the idea that defects in the HSC microenvironment may play a role either in MDS or in AML development6789. For instance, interactions between MSC from the leukemic stem cell niche and malignant cells are critical components of resistance to many chemotherapy agents101112.…”