The tetraspanin CD82 regulates bone marrow homing and engraftment of hematopoietic stem and progenitor cells

Saito-Reis, Chelsea A.; Marjon, Kristopher D.; Pascetti, Erica M; Floren, Muskan; Gillette, Jennifer M.

doi:10.1091/mbc.e18-05-0305

Cited by 20 publications

(18 citation statements)

References 58 publications

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“…In CD82 knockout mice, HSPCs from the knockout exhibited stem cell migratory and spreading defects. This was found to be related to hyeractivation of Rac 1 GTPases in these CD82 knockout HSPCs since Rac1 inhibition rescued homing capacity 51 …”

Section: Hspc Homing: Rolling Adhesion and Transmigrationmentioning

confidence: 91%

Stem cell homing: From physiology to therapeutics

2020

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Stem cell homing is a multistep endogenous physiologic process that is also used by exogenously administered hematopoietic stem and progenitor cells (HSPCs). This multistep process involves cell migration and is essential for hematopoietic stem cell transplantation. The process can be manipulated to enhance ultimate engraftment potential, and understanding stem cell homing is also important to the understanding of stem cell mobilization. Homing is also of potential importance in the recruitment of marrow mesenchymal stem and stromal cells (MSCs) to sites of injury and regeneration. This process is less understood but assumes importance when these cells are used for repair purposes. In this review, the process of HSPC and MSC homing is examined, as are methods to enhance this process.

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Section: Hspc Homing: Rolling Adhesion and Transmigrationmentioning

confidence: 91%

Stem cell homing: From physiology to therapeutics

2020

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“…Similarly, a previous study focused on CD151 identified interactions with integrins β1 and αIIbβ3 as critical for promoting HSPC adhesion to various ECMs ( Fitter et al, 1999 ) and both CD81 and CD82 were shown to mediate α4β1 adhesion of erythroblasts to Vascular Cell Adhesion molecule-1 ( Spring et al, 2013 ). More recently, our work using the CD82KO mouse model identified a homing and engraftment defect of HSPCs, which was linked to altered Rac1 activity ( Saito-Reis et al, 2018 ), further illustrating that CD82 may serve as a therapeutic target to modulate HSPC adhesion and migration.…”

Section: Tetraspanins: Hsc Adhesion Migration and Signaling Within mentioning

confidence: 83%

“…A number of tetraspanin knock out (KO) mice have been generated, but up until now, only two have displayed an HSC defect. CD82KO animals exhibit a reduction in LT-HSCs, resulting from increased stem cell activation and reduced quiescence signaling ( Hur et al, 2016 ; Saito-Reis et al, 2018 ). In contrast, HSCs from CD81KO mice appear to proliferate similarly to control animals, but demonstrate a reduced ability to reenter quiescence after stimulation ( Lin et al, 2011 ).…”

Section: Tetraspanins: Hsc Quiescencementioning

confidence: 99%

Tetraspanin Scaffold Proteins Function as Key Regulators of Hematopoietic Stem Cells

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Saito-Reis

Gillette

2020

Front. Cell Dev. Biol.

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Hematopoietic stem and progenitor cells (HSPCs) are responsible for the development, maintenance, and regeneration of all the blood forming cells in the body, and as such, are critical for a number of patient therapies. For successful HSPC transplantation, stem cells must traffic through the blood and home to the bone marrow (BM) microenvironment or "niche," which is composed of soluble factors, matrix proteins, and supportive cells. HSPC adhesion to, and signaling with, cellular and extracellular components of the niche provide instructional cues to balance stem cell selfrenewal and differentiation. In this review, we will explore the regulation of these stem cell properties with a focus on the tetraspanin family of membrane proteins. Tetraspanins are molecular scaffolds that uniquely function to distribute proteins into highly organized microdomains comprising adhesion, signaling, and adaptor proteins. As such, tetraspanins contribute to many aspects of cell physiology as mediators of cell adhesion, trafficking, and signaling. We will summarize the many reports that identify tetraspanins as markers of specific HSPC populations. Moreover, we will discuss the various studies establishing the functional importance of tetraspanins in the regulation of essential HSPC processes including quiescence, migration, and niche adhesion. When taken together, studies outlined in this review suggest that several tetraspanins may serve as potential targets to modulate HSPC interactions with the BM niche, ultimately impacting future HSPC therapies.

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“…The tetraspanin CD82 was also found to be upregulated in several leukemias, including AML ( 16 ), with aberrant CD82 expression detected specifically in chemotherapy-resistant CD34 + /CD38 − AML cells ( 17 , 18 ). Additionally, work from our group identified CD82 as a key regulator of AML cell homing to the bone marrow ( 19 ) and demonstrated that CD82 modulates the spatial and temporal dynamics of Protein Kinase C α (PKCα) signaling in AML ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

et al. 2020

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A principal challenge in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. As such, there remains a critical need to identify key regulators of chemotherapy resistance in AML. In this study, we demonstrate that the membrane scaffold, CD82, contributes to the chemoresistant phenotype of AML. Using an RNA-seq approach, we identified the increased expression of the tetraspanin family member, CD82, in response to the chemotherapeutic, daunorubicin. Analysis of the TARGET and BEAT AML databases identifies a correlation between CD82 expression and overall survival of AML patients. Moreover, using a combination of cell lines and patient samples, we find that CD82 overexpression results in significantly reduced cell death in response to chemotherapy. Investigation of the mechanism by which CD82 promotes AML survival in response to chemotherapy identified a crucial role for enhanced protein kinase c alpha (PKCα) signaling and downstream activation of the β1 integrin. Additionally, analysis of β1 integrin clustering by super-resolution imaging demonstrates that CD82 expression promotes the formation of dense β1 integrin membrane clusters. Lastly, evaluation of survival signaling following daunorubicin treatment identified robust activation of p38 mitogen-activated protein kinase (MAPK) downstream of PKCα and β1 integrin signaling when CD82 is overexpressed. Together, these data propose a mechanism where CD82 promotes chemoresistance by increasing PKCα activation and downstream activation/clustering of β1 integrin, leading to AML cell survival via activation of p38 MAPK. These observations suggest that the CD82-PKCα signaling axis may be a potential therapeutic target for attenuating chemoresistance signaling in AML.

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The tetraspanin CD82 regulates bone marrow homing and engraftment of hematopoietic stem and progenitor cells

Cited by 20 publications

References 58 publications

Stem cell homing: From physiology to therapeutics

Stem cell homing: From physiology to therapeutics

Tetraspanin Scaffold Proteins Function as Key Regulators of Hematopoietic Stem Cells

Tetraspanin CD82 drives acute myeloid leukemia chemoresistance by modulating protein kinase C alpha and β1 integrin activation

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