Cripto Regulates Hematopoietic Stem Cells as a Hypoxic-Niche-Related Factor through Cell Surface Receptor GRP78

Miharada, Kenichi; Karlsson, Göran; Rehn, Matilda; Rörby, Emma; Siva, Kavitha; Cammenga, Jörg; Karlsson, Stefán

doi:10.1016/j.stem.2011.07.016

Cited by 154 publications

(142 citation statements)

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“…Interestingly, low oxygen levels stabilize and activate HIF, 44 which is important for the maintenance of hematopoietic stem cells and promotes self-renewal of embryonic stem cells. 45,46 Therefore, the enrichment of hypoxia-, HIF1α-targets and hematopoietic stem cell-associated genes in our AKT-inhibited CD8 + T cells could indicate improved self-renewal capacity and good functionality in low oxygen environments.…”

Section: Discussionmentioning

confidence: 92%

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Mousset

Hobo

et al. 2018

OncoImmunology

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Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.

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Section: Discussionmentioning

confidence: 92%

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Mousset

Hobo

et al. 2018

OncoImmunology

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“…Cripto is associated with the pluripotent status of both human and mouse ES cells (ESCs) (3), and it acts as a key player in the signaling networks orchestrating ESC differentiation (4). Intriguingly, it has been recently suggested that Cripto may serve as a regulator to control dormancy of hematopoietic stem cells (5).…”

mentioning

confidence: 99%

Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin

Guardiola

Lafuste

Brunelli

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. However, our understanding of the molecular mechanisms underlying satellite cell activation is still largely undefined. Here, we show that Cripto, a regulator of early embryogenesis, is a novel regulator of muscle regeneration and satellite cell progression toward the myogenic lineage. Conditional inactivation of cripto in adult satellite cells compromises skeletal muscle regeneration, whereas gain of function of Cripto accelerates regeneration, leading to muscle hypertrophy. Moreover, we provide evidence that Cripto modulates myogenic cell determination and promotes proliferation by antagonizing the TGF-β ligand myostatin. Our data provide unique insights into the molecular and cellular basis of Cripto activity in skeletal muscle regeneration and raise previously undescribed implications for stem cell biology and regenerative medicine. myogenic commitment | skeletal muscle stem cells | teratocarcinoma derived growth factor-1 (TDGF-1) | growth differentiation factor-8 (GDF-8)

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“…Since the osteoblasts do Cripto is protein that blocks TGF-β signaling is binding with GRP78, also known as HSPA5, on hypoxic HSCs and activate P13K-Akt-pathway leading to the maintenance of HSCs localized in the endosteal niche. Blockade of Cripto-GRP78-signaling by the blocking antibodies N-20 mobilizes HSCs migration from the endosteal region into central part of BM but cannot alter the HSCs number in the BM, peripheral blood and spleen, showing that local mobilization can take place without into the peripheral blood [223]. The endosteal cells expressing Cripto include mostly ALCAM -Sca-1 + and, to a lesser degree, ALCAM -Sca-1 -cells [223].…”

Section: Macrophagesmentioning

confidence: 99%

Structural-functional organisation of the bone marrow hematopoietic stem cells niches

Nikolskaya¹,

Butenko²

2016

JCOT

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This article focuses on (1) the analysis of the structural-functional organization of bone marrow niches of the hematopoietic stem cells, (2) the role of the intercellular contact interactions and humoral regulation factors in these niches, in particular CXCL12, SCF and TGFβ,and (3) KEYWORDS: bone marrow, hematopoietic stem cell niche, multipotent stromal cells, hematopoiesisMaksimov and finally established at the end of the past century, it is not only the number but also entire known diversity of cell elements of immune and blood systems originate from only one type of the progenitor elements -the HSCs (unitary theory) [2].Life force and productivity of the HSCs is proved, for example, by the fact that 99.9 % of all blood-generating cells, HSCs included, in the irradiated mice can perish, and the surviving stem cells rapidly renew blood formation, including proper population as well as all types of the committed progenitors [3]. Along same sequence, the fact of non-exhaustion of blood formation after repeated damaging exposures is explained by the presence and functioning of the HSCs [1].The specialized cells of adult and fetal periods of ontogenesis, residing in the bone marrow (BM) in the quiescent state and capable, together with blood-forming microenvironment, to realize underlying programs for self-maintenance and multipotency allowing them (with maintained amount of HSCs) to release necessary amount of cells into differentiation along various directions that ultimately leads to the formation of all forms of blood elements, including immune system cells. It should be noted that the self-maintenance is not identical to the immortality. Stem cells are characterized by sufficiently long life, commensurable with entire organism's life course. Several genetic regulatory programs have been established which are of great importance in the process of HSCs self-maintenance. It is also known that stem cells in various tissues are controlled by common genetic programs maintaining their nature [4,5].It is theorized that stem cells are the clonogenic units which under certain conditions can be increased in their number at the expense Immune system is the structural-functional and interrelated commonness of the hematopoietic and stromal cells. Different in their origin, structure and functions, the populations and subpopulations of lymphoid and myeloid cells make a complete wholeness in the definite tissues and organs where they closely cooperate with non-hematopoietic elements. Constant and strictly regulated intensity of hematopoiesis with production of various cell types is also conditioned and controlled by cooperation of the hematopoietic and stromal cells. Timely repopulation of the immune system with hematopoietic cells-precursors, lymphocytes, leucocytes and stromal cells, newly maturing in the bone marrow, is the main condition for effective immune system functioning. The number of cells formed per time unit is plentiful. According to the given data, nearly 10 11 neutrophils (about 100 g of mass) per...

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Cripto Regulates Hematopoietic Stem Cells as a Hypoxic-Niche-Related Factor through Cell Surface Receptor GRP78

Cited by 154 publications

References 52 publications

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin

Structural-functional organisation of the bone marrow hematopoietic stem cells niches

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Cripto Regulates Hematopoietic Stem Cells as a Hypoxic-Niche-Related Factor through Cell Surface Receptor GRP78

Cited by 154 publications

References 52 publications

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

Cripto regulates skeletal muscle regeneration and modulates satellite cell determination by antagonizing myostatin

Structural-functional organisation of the bone marrow hematopoietic stem cells niches

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Product

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About

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy