All ETDs from UAB

Advisory Committee Chair

Robert Welner

Advisory Committee Members

Susan Bellis

Ravi Bhatia

Amjad Javed

Christopher Klug

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The bone marrow is a complex organization of hematopoietic and nonhematopoietic cells that form niches to maintain systemic homeostasis during stress and disease. Stromal cells are non-hematopoietic cells first proposed in 1978 in the bone marrow to be essential for hematopoietic stem cells (HSC). Since then, mesenchymal stromal cells (MSC) have been shown to be critical for the HSC self-renewal, retention, and differentiation through chemokines, cytokines, and adhesion molecules. However, like HSCs, MSCs are multipotent progenitors that differentiate into osteoblasts, adipocytes, and chondrocytes to from tissues of the skeletal, endocrine, and connective systems. These multipotent progenitors are tightly regulated in their differentiation to maintain homeostatic balance. Inflammatory conditions are known to disrupt mature populations of osteoblasts and adipocytes with little focus on MSCs. MSCs are known to have an immune modulatory role and express receptors for inflammatory signals. However, how MSCs are functionally rewired is unknown. Here we propose that inflammation disrupts the lineage output through transcriptional rewiring of MSCs. We observe that acute inflammation from lipopolysaccharide (LPS) and polyionsinic: polycytidylic acid (Poly(I:C)) structurally IV alters mature bone like that seen in chronic inflammatory disease. The structural changes can be traced back to changes in the progenitor pool of cells as proposed. There is a natural propensity of MSCs to differentiate into osteoblasts and adipocytes after exposure to acute inflammatory stimulus. We see that upregulation of IL-1b and increase in MAPK signaling is partially responsible for the response. From this we highlight that MSCs respond to inflammatory stimulus in the bone marrow like the hematopoietic system. The foundations provided from stromal cell response to acute inflammation allows for the expansion into complex inflammatory disease such as acute myeloid leukemia (AML). This highly inflammatory disease is known to disrupt the stromal cell environment to promote leukemic progression at the detriment of healthy HSCs. Understanding how inflammation plays a role in MSCs maintenance and lineage progression allows for therapeutic intervention. Targeting of cytokines impacting stromal cells will hinder rewiring making a less hospitable environment for leukemic cells.

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