Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders

Abstract

: Mesenchymal stromal cells (MSCs) are crucial elements in the bone marrow (BM) niche where they provide physical support and secrete soluble factors to control and maintain hematopoietic stem progenitor cells (HSPCs). Given their role in the BM niche and HSPC support, MSCs have been employed in the clinical setting to expand ex-vivo HSPCs, as well as to facilitate HSPC engraftment in vivo. Specific alterations in the mesenchymal compartment have been described in hematological malignancies, as well as in rare genetic disorders, diseases that are amenable to allogeneic hematopoietic stem cell transplantation (HSCT), and ex-vivo HSPC-gene therapy (HSC-GT). Dissecting the in vivo function of human MSCs and studying their biological and functional properties in these diseases is a critical requirement to optimize transplantation outcomes. In this review, the role of MSCs in the orchestration of the BM niche will be revised, and alterations in the mesenchymal compartment in specific disorders will be discussed, focusing on the need to correct and restore a proper microenvironment to ameliorate transplantation procedures, and more in general disease outcomes.

Keywords: bone marrow niche; ex-vivo gene therapy; hematopoietic stem and progenitor cells; hematopoietic stem cell transplantation; mesenchymal stromal cells.

Figure 1

Schematic representation of a model describing mesenchymal stromal cells (MSCs) in the human bone marrow (BM) niche. In the human BM niche, different subtypes of MSCs interact with hematopoietic stem cells (HSCs) in the different perivascular regions and show specific functional characteristics. In particular, classification determinants (CD) 271 and CD271⁺/CD146^-/low MSCs are bone-lining MSCs associated with long-term (LT)-HSCs in low oxygen areas, whereas CD146⁺ and CD271⁺/CD146⁺ are located around the BM sinusoids in association with activated and fast-proliferating HSCs. Abbreviations: BM—bone marrow; MSC—mesenchymal stromal cells; HSC—hematopoietic stem cell; CD—classification determinant; LT—long-term; HSPC—hematopoietic stem and progenitor cell.

Figure 2

Representative image describing the role of the NOTCH/JAG1 pathway in AML-MSCs of a model describing MSCs in human BM niche. NOTCH/JAG1 signaling plays a fundamental role in the MSC-dependent control of tumor initiation, growth, and chemoresistance. NOTCH1, JAG1, and HES1 are overexpressed in AML-MSCs, promoting survival of tumor cells treated with chemotherapeutic agents. Abbreviations: NOTCH—Notch Homolog 1, Translocation-Associated; JAG1—of jagged canonical Notch ligand 1; AML-MSCs—acute myeloid leukemia derived mesenchymal stroma cells; MSC—mesenchymal stromal cells; BM—bone marrow; HES1—hairy and enhancer of split 1; KITLG—KIT ligand; LSCs—leukemic stem cells; HSPCs—hematopoietic stem and progenitor cells.

Figure 3

Representative pictures of novel therapeutic strategies targeting the malignant BM niche. Denosumab reduces osteolytic lesions by inhibiting the RANK–RANKL pathway (1). The mobilization of leukemic stem cells by plerixafor increase the efficacy of chemotherapy (2). Inhibition of DKK-1 prevents bone damage by inducing osteoblast differentiation (3). Inhibition of IGF1-R blocks the proliferation cascade activated by IGF1 released by osteoblast and tumor cells (4). Abbreviations: RANK—receptor activator of nuclear factor-kappa-Β ligand; RANKL—RANK ligand; DKK-1—Dickkopf-related protein 1; IGF1—insulin growth factor 1; IGF1-R—IGF1 receptor; BM—bone marrow; HD-MSCs—healthy donor-derived mesenchymal stromal cells; MM-MSCs—multiple myeloma-derived mesenchymal stromal cells.

Figure 4

Representative pictures of pathological BM niches in PIDs. MSCs derived from primary immune-deficient (PIDs) patients, suffering from frequent infection and extensive inflammation, which compromises the capacity of MSCs to control T cell proliferation and alters their immunoregulatory profile. Abbreviations: BM—bone marrow; PID—primary immunodeficiencies; MSCs—mesenchymal stromal cells; TLR—Toll-like receptor.

Figure 5

Representative pictures of pathological BM niches in MPSIH patients. MSCs derived from mucopolysaccharidosis type I- Hurler–syndrome (MPSIH) patients. The accumulation of Glycosaminoglycans (GAGs) causes multiorgan dysfunction, including bone defects. The upregulation of RANKL/RANK/OPG pathway causes unbalanced bone remodeling. Abbreviations: BM—bone marrow; MPSIH-MSCs—Mucopolysaccharidosis type I Hurler–derived mesenchymal stroma cells; RANK—receptor activator of nuclear factor-kappa-Β ligand; RANKL—RANK ligand; OPG—osteoprotegerin.

Figure 6

Representative pictures of pathological BM niches in BT patients. MSCs derived from Beta Thalassemia (BT) patients. Iron accumulation in the BM leads to increased levels of Radical Oxygen Species (ROS), which causes a pauperization of the primitive MSC pool and alters the MSC hematopoietic supportive function. Abbreviations: BM—bone marrow; BT-MSCs—beta-thalassemia derived mesenchymal stroma cells; Fe²⁺—iron, ferrous ion.