The role of CD44 in fetal and adult hematopoietic stem cell regulation

Haematopoietic stem cells (HSC) first arise during development in the aorta-gonad-mesonephros (AGM) region of the embryo from a population of haemogenic endothelial cells which undergo endothelial-to-haematopoietic transition (EHT). Despite the progress achieved in recent years, the molecular mechanisms driving EHT are still poorly understood, especially in human where the AGM region is not easily accessible. In this study, we took advantage of a human pluripotent stem cell (hPSC) differentiation system and single-cell transcriptomics to recapitulate EHT in vitro and uncover mechanisms by which the haemogenic endothelium generates early haematopoietic cells. We show that most of the endothelial cells reside in a quiescent state and progress to the haematopoietic fate within a defined time window, within which they need to re-enter into the cell cycle. If cell cycle is blocked, haemogenic endothelial cells lose their EHT potential and adopt a non-haemogenic identity. Furthermore, we demonstrated that CDK4/6 and CDK1 play a key role not only in the transition but also in allowing haematopoietic progenitors to establish their full differentiation potential. Therefore, we propose a direct link between the molecular machineries that control cell cycle progression and EHT.

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“…2c ). CD44 was previously shown to be expressed on IAHCs emerging during EHT in both human and mouse (34, 35, 36).…”

Section: Resultsmentioning

confidence: 99%

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Canu

Athanasiadis

Grandy

et al. 2020

Preprint

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“…The interaction between extracellular matrix (ECM) components and cell surface receptors on HSC, such as hyaluronic acid and its receptor CD44 (Figure ), is also part of the trafficking and homing mechanisms occurring in the hematopoietic niche . The relevance of ECM components was evidenced by the higher expansion levels observed when UCB CD34 + stem/progenitor cells were co‐cultured with an acellular matrix derived from a human BM stromal line …”

Section: The Bm Microenvironmentmentioning

confidence: 99%

Hematopoietic Niche – Exploring Biomimetic Cues to Improve the Functionality of Hematopoietic Stem/Progenitor Cells

Costa

Soure

Cabral

et al. 2017

Biotechnology Journal

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The adult bone marrow (BM) niche is a complex entity where a homeostatic hematopoietic system is maintained through a dynamic crosstalk between different cellular and non-cellular players. Signaling mechanisms triggered by cell-cell, cell-extracellular matrix (ECM), cell-cytokine interactions, and local microenvironment parameters are involved in controlling quiescence, self-renewal, differentiation, and migration of hematopoietic stem/progenitor cells (HSPC). A promising strategy to more efficiently expand HSPC numbers and tune their properties ex vivo is to mimic the hematopoietic niche through integration of adjuvant stromal cells, soluble cues, and/or biomaterial-based approaches in HSPC culture systems. Particularly, mesenchymal stem/stromal cells (MSC), through their paracrine activity or direct contact with HSPC, are thought to be a relevant niche player, positioning HSPC-MSC co-culture as a valuable platform to support the ex vivo expansion of hematopoietic progenitors. To improve the clinical outcome of hematopoietic cell transplantation (HCT), namely when the available HSPC are present in a limited number such is the case of HSPC collected from umbilical cord blood (UCB), ex vivo expansion of HSPC is required without eliminating the long-term repopulating capacity of more primitive HSC. Here, we will focus on depicting the characteristics of co-culture systems, as well as other bioengineering approaches to improve the functionality of HSPC ex vivo.

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“…We also determined the expression of CD44, a Wnt-associated protein 43 that is involved in HSPC lodging to the endosteal region after transplant. 44 CD44 was present at comparable levels on the surface of both Ctnnb1 fl/fl and Ctnnb1 Δ/Δ FL HSPCs ( Figure 6G), indicating that Ctnnb1 Δ/Δ FL HSPCs harbor other defects that prevent their efficient short-term engraftment.…”

Section: Lack Of -Catenin Results In Decreased Quiescence and Increasmentioning

confidence: 92%

“…There was no specific decrease in the homing of CD150 + Sca‐1 + HSPCs or more mature CD150 − CD48 + multipotent progenitors, suggesting that the defective short‐term repopulation is more related to a problem with HSPC engraftment and expansion. We also determined the expression of CD44, a Wnt‐associated protein that is involved in HSPC lodging to the endosteal region after transplant . CD44 was present at comparable levels on the surface of both Ctnnb1 fl/fl and Ctnnb1 Δ/Δ FL HSPCs (Figure G), indicating that Ctnnb1 Δ/Δ FL HSPCs harbor other defects that prevent their efficient short‐term engraftment.…”

Section: Resultsmentioning

confidence: 99%

Frontline Science: Wnt/β-catenin pathway promotes early engraftment of fetal hematopoietic stem/progenitor cells

Kwarteng

Hétu-Arbour

Heinonen

2018

Journal of Leukocyte Biology

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The switch from fetal to adult hematopoietic stem/progenitor cells (HSPCs) is associated with profound changes in several genetic programs. Although HSPC ageing corresponds to alterations in Wnt signaling, relatively little is known about the relative roles of different Wnt signaling pathways in HSPC ontogeny. We hypothesized that proliferating fetal HSPCs would be more dependent on canonical β-catenin-dependent Wnt signaling when compared to quiescent adult bone marrow HSPCs. We have compared here Wnt signaling activities in murine fetal and adult HSPCs and demonstrate a shift from Wnt/β-catenin-dependent signaling in fetal liver HSPCs to more predominantly noncanonical Wnt/polarity signaling in adult HSPCs. β-Catenin was selectively required for fetal HSPC competitiveness shortly after transplant, and protected cells from oxidative stress. Our results emphasize the complexity of Wnt signaling dynamics in HSPC maintenance and function.

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The role of CD44 in fetal and adult hematopoietic stem cell regulation

Cited by 62 publications

References 65 publications

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Analysis of Endothelial-to-Haematopoietic Transition at the Single Cell Level identifies Cell Cycle Regulation as a Driver of Differentiation

Hematopoietic Niche – Exploring Biomimetic Cues to Improve the Functionality of Hematopoietic Stem/Progenitor Cells

Frontline Science: Wnt/β-catenin pathway promotes early engraftment of fetal hematopoietic stem/progenitor cells

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