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.

Mesenchymal Stem/Stromal Cells in Immunity and Disease: A Better Understanding for an Improved Use

“…The review of Crippa, S. et al revised the role of MSCs in the orchestration of the BM niche, and discussed possible alterations in the mesenchymal compartment in specific disorders. They focused on the need to correct and restore a proper microenvironment to ameliorate transplantation procedures, and more general disease outcomes [12]. Batsali, A.K.…”

Mesenchymal Stromal Cells in Neuroblastoma: Exploring Crosstalk and Therapeutic Implications

“…MSC co-transplantation can be used to support the nesting of HSPCs in the BM hematopoietic niche, to reduce the inflammation of damaged tissue and thus to sustain an overall functional BM niche [ 187 ]. Although the benefits of MSC co-transplantation to enhance engraftment in allogeneic HSC transplantation and to prevent graft-versus-host disease have been studied extensively [ 188 ], its use in the autologous context, as common in NB, remains largely unexplored [ 189 , 190 ].…”

Role of ex vivo Expanded Mesenchymal Stromal Cells in Determining Hematopoietic Stem Cell Transplantation Outcome

“…However, the MSC release of supportive factors is the principal molecular mechanism regulating HSPCs\homeostasis in vivo , within the BM niche, and ex vivo , in MSC-based co-culture systems and when MSCs are co-infused to sustain HSPCs in HSTC pre-clinical and clinical models ( Crippa et al, 2019 ). The role of MSC secretome ( Liu et al, 2018 ) and MSC-derived extracellular vesicles ( Batsali et al, 2020 ) also demonstrates the predominance of MSC paracrine activity in sustaining HSPC function.…”

“…However, in vitro TNFα addition was sufficient to reverse MSC immunosuppressive effects, suggesting that environmental parameters and the microenvironment, in general, may influence and affect the immunomodulatory properties of MSCs ( Djouad et al, 2005 ). Still, MSC treatment in humans has shown promising outcomes in several conditions, including GvHD ( Le Blanc et al, 2004 ) and engraftment promotion ( Lazarus et al, 1995 ; Koc et al, 2000 ), thanks to their potent immunosuppressive role but also in some rare diseases in which MSCs may be responsible of ameliorating the disease pathology in specific tissues ( Crippa et al, 2019 ). Therefore, a better understanding of MSCs’ immunomodulatory role might be crucial to develop novel and effective therapeutic strategies for a broad range of diseases.…”