Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis—Masters of Survival and Clonality?

Abstract

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the “reprogramming” of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs.

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

“…T-cell exhaustion is thereby induced by consistent antigen exposure leading to altered T-cell differentiation, loss of effector functions and anergy as well as upregulation and coexpression of inhibitory receptors that are also used as exhaustion markers ( eg programmed death 1 (PD1)), and alterations of other key characteristics (for reviews see [21–23]). In addition, cancer cells cleverly expand regulatory T-cells (Tregs) [24] and further B-, natural killer- and dendritic-regulatory cells (for review see [25]) in order to prime the microenvironment towards a tumor supportive milieu. Under normal conditions, immune checkpoint molecules serve to regulate T-cell responses, which is necessary to avoid uncontrolled expansion resulting in organ destruction and fatal outcomes.…”

“…Under normal conditions, immune checkpoint molecules serve to regulate T-cell responses, which is necessary to avoid uncontrolled expansion resulting in organ destruction and fatal outcomes. Tumor cells use these intrinsic ‘brakes’ of the immune system as immune escape mechanisms by inducing functionally exhausted T-cells [15, 25]. …”

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“…Similarly, several reports have described critical molecular changes in the stroma of solid tumors [2][3][4] and more recently; it has been shown in colorectal cancer (CRC) that genes expressed by stromal cells are better predictors of response to therapy and disease prognosis than genes expressed by epithelial tumor cells [4]. In hematological malignancies, BM-MSC from myelodysplastic syndrome (MDS) and AML patients often exhibit altered gene expression profiles, an aberrant Priority Research Paper phenotype, and abnormal functional properties compared to normal donor-derived BM-MSC [5]. Although many studies support these findings [6][7][8], little is known about how genetic aberrations in tumor cells differentially impact the genetic and phenotypic changes in the tumor stroma.…”

An Update on the Components and Functions of Bone Marrow Niche

“…This dynamic microenvironment provides all the cellular components and molecular signals that are essential for HSC maintenance and ensures the rapid blood production for daily needs [1,2]. Most of our new vision about niche comes from advanced imaging technologies, different transgenic mouse models and in vivo lineage tracing studies.…”

“…These soluble factors include stem cell factor (SCF), transforming growth factor (TGF-β), C-X-C motif chemokine ligand 12 (CXCL12), angiopoietin-1, granulocyte-colony stimulating factor (G-CSF), Wnt ligands, and thrombopoietin (TPO) [1,3]. In the bone marrow microenvironment, two distinct niches have been proposed.…”