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Molecular mechanisms underlying adhesion and migration of hematopoietic stem cells.

ABSTRACT: Hematopoietic stem cell transplantation is the most powerful treatment modality for a large number of hematopoietic malignancies, including leukemia. Successful hematopoietic recovery after transplantation depends on homing of hematopoietic stem cells to the bone marrow and subsequent lodging of those cells in specific niches in the bone marrow. Migration of hematopoietic stem cells to the bone marrow is a highly regulated process that requires correct regulation of the expression and activity of various molecules including chemoattractants, selectins and integrins. This review will discuss recent studies that have extended our understanding of the molecular mechanisms underlying adhesion, migration and bone marrow homing of hematopoietic stem cells.

SUBMITTER: Sahin AO

PROVIDER: S-EPMC3364136 | biostudies-literature | 2012 Jan-Feb

REPOSITORIES: biostudies-literature

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Molecular mechanisms underlying adhesion and migration of hematopoietic stem cells.

Sahin Aysegul Ocal AO Buitenhuis Miranda M

Cell adhesion & migration 20120101 1

Hematopoietic stem cell transplantation is the most powerful treatment modality for a large number of hematopoietic malignancies, including leukemia. Successful hematopoietic recovery after transplantation depends on homing of hematopoietic stem cells to the bone marrow and subsequent lodging of those cells in specific niches in the bone marrow. Migration of hematopoietic stem cells to the bone marrow is a highly regulated process that requires correct regulation of the expression and activity o ...[more]

PMID: 22647939

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Project description:BACKGROUND: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells. METHODOLOGY/PRINCIPAL FINDINGS: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation. CONCLUSIONS/SIGNIFICANCE: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases.

Project description:Hematopoietic stem cells (HSC) could have several fates in the body; viz. self-renewal, differentiation, migration, quiescence, and apoptosis. These fate decisions play a crucial role in maintaining homeostasis and critically depend on the interaction of the HSCs with their micro-environmental constituents. However, the physiological cues promoting these interactions in vivo have not been identified to a great extent. Intense research using various in vitro and in vivo models is going on in various laboratories to understand the mechanisms involved in these interactions, as understanding of these mechanistic would greatly help in improving clinical transplantations. However, though these elegant studies have identified the molecular interactions involved in the process, harnessing these interactions to the recipients' benefit would ultimately depend on manipulation of environmental cues initiating them in vivo: hence, these need to be identified at the earliest. HSCs reside in the bone marrow, which is a very complex tissue comprising of various types of stromal cells along with their secreted cytokines, extra-cellular matrix (ECM) molecules and extra-cellular vesicles (EVs). These components control the HSC fate decision through direct cell-cell interactions - mediated via various types of adhesion molecules -, cell-ECM interactions - mediated mostly via integrins -, or through soluble mediators like cytokines and EVs. This could be a very dynamic process involving multiple transient interactions acting concurrently or sequentially, and the adhesion molecules involved in various fate determining situations could be different. If the switch mechanisms governing these dynamic states in vivo are identified, they could be harnessed for the development of novel therapeutics. Here, in addition to reviewing the adhesion molecules involved in the regulation of HSCs, we also touch upon recent advances in our understanding of the physiological cues known to initiate specific adhesive interactions of HSCs with the marrow stromal cells or ECM molecules and EVs secreted by them.

Dataset Information

Molecular mechanisms underlying adhesion and migration of hematopoietic stem cells.

Publications

Molecular mechanisms underlying adhesion and migration of hematopoietic stem cells.

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