Emerging trends in chromatin remodeler plasticity in mesenchymal stromal cell function

Abstract

Emerging evidences highlight importance of epigenetic regulation and their integration with transcriptional and cell signaling machinery in determining tissue resident adult pluripotent mesenchymal stem/stromal cell (MSC) activity, lineage commitment, and multicellular development. Histone modifying enzymes and large multi‐subunit chromatin remodeling complexes and their cell type‐specific plasticity remain the central defining features of gene regulation and establishment of tissue identity. Modulation of transcription factor expression gradient ex vivo and concomitant flexibility of higher order chromatin architecture in response to signaling cues are exciting approaches to regulate MSC activity and tissue rejuvenation. Being an important constituent of the adult bone marrow microenvironment/niche, pathophysiological perturbation in MSC homeostasis also causes impaired hematopoietic stem/progenitor cell function in a non‐cell autonomous mechanism. In addition, pluripotent MSCs can function as immune regulatory cells, and they reside at the crossroad of innate and adaptive immune response pathways. Research in the past few years suggest that MSCs/stromal fibroblasts significantly contribute to the establishment of immunosuppressive microenvironment in shaping antitumor immunity. Therefore, it is important to understand mesenchymal stromal epigenome and transcriptional regulation to leverage its applications in regenerative medicine, epigenetic memory‐guided trained immunity, immune‐metabolic rewiring, and precision immune reprogramming. In this review, we highlight the latest developments and prospects in chromatin biology in determining MSC function in the context of lineage commitment and immunomodulation.

ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment

“…If this is the case, a stable mechanism for gene expression regulation, such as an epigenetic change, may be involved. Interestingly, although this hypothesis awaits experimental validation, epigenetic modulation of MSC gene expression has been repeatedly described in hematological malignancies 47,48 .…”

Epigenetic therapy targeting bone marrow mesenchymal stem cells for age-related bone diseases

“…Before genes are transcribed, chromatin is transformed into a looser state. This process requires the participation of the chromatin remodeling complex, which uses ATP as energy to change the position and composition of nucleosomes, thereby regulating chromatin structure and gene expression [ 90 , 91 ]. SWI/SNF is a type of chromatin remodeling complex, while mammalian brahma (BRM), an ATPase, is a component of SWI/SNF.…”

Cell‐to‐cell contact‐mediated regulation of tumor behavior in the tumor microenvironment

“… 4 This transition induces tumor progressive activities of stromal cells through epigenetic modifications and locally acting signals, which serves as a critical driver of malignancy. 5 Moreover, the tumor microenvironment exhibits spatiotemporally promotive or suppressive functions that contribute to tumor progression. 6 …”

“…However, during tumor progression, a subpopulation of cancer cells resist stroma‐mediated suppression, and begin to reprogram and remodel the surrounding stroma to support further tumor progression 4 . This transition induces tumor progressive activities of stromal cells through epigenetic modifications and locally acting signals, which serves as a critical driver of malignancy 5 . Moreover, the tumor microenvironment exhibits spatiotemporally promotive or suppressive functions that contribute to tumor progression 6 …”

“…4 This transition induces tumor progressive activities of stromal cells through epigenetic modifications and locally acting signals, which serves as a critical driver of malignancy. 5 Moreover, the tumor microenvironment exhibits spatiotemporally promotive or suppressive functions that contribute to tumor progression. 6 Numerous studies have shown that classical paracrine and endocrine signaling via the secretion of soluble factors, including cytokines and growth factors, into the extracellular space contribute to the regulation of the tumor microenvironment to suppress or promote tumor progression.…”