scholarly journals Understanding the Journey of Human Hematopoietic Stem Cell Development

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Akhilesh Kumar ◽  
Saritha S. D’Souza ◽  
Abir S. Thakur
Keyword(s):  
Stem Cells ◽  
Blood Cell ◽  
Hematopoietic Stem Cells ◽  
Human Blood ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Hematopoietic Stem ◽  
Hematopoietic Development

Hematopoietic stem cells (HSCs) surface during embryogenesis leading to the genesis of the hematopoietic system, which is vital for immune function, homeostasis balance, and inflammatory responses in the human body. Hematopoiesis is the process of blood cell formation, which initiates from hematopoietic stem/progenitor cells (HSPCs) and is responsible for the generation of all adult blood cells. With their self-renewing and pluripotent properties, human pluripotent stem cells (hPSCs) provide an unprecedented opportunity to createin vitromodels of differentiation that will revolutionize our understanding of human development, especially of the human blood system. The utilization of hPSCs provides newfound approaches for studying the origins of human blood cell diseases and generating progenitor populations for cell-based treatments. Current shortages in our knowledge of adult HSCs and the molecular mechanisms that control hematopoietic development in physiological and pathological conditions can be resolved with better understanding of the regulatory networks involved in hematopoiesis, their impact on gene expression, and further enhance our ability to develop novel strategies of clinical importance. In this review, we delve into the recent advances in the understanding of the various cellular and molecular pathways that lead to blood development from hPSCs and examine the current knowledge of human hematopoietic development. We also review howin vitrodifferentiation of hPSCs can undergo hematopoietic transition and specification, including major subtypes, and consider techniques and protocols that facilitate the generation of hematopoietic stem cells.

scholarly journals Hematopoietic specification from human pluripotent stem cells: current advances and challenges toward de novo generation of hematopoietic stem cells

Blood ◽  
2013 ◽  
Vol 122 (25) ◽  
pp. 4035-4046 ◽  
Author(s):  
Igor I. Slukvin
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Pluripotent Stem Cells ◽  
De Novo ◽  
Human Pluripotent Stem Cells ◽  
Cellular Reprogramming ◽  
Hematopoietic Stem ◽  
Hematopoietic Development ◽  
Cellular Pathways

Abstract Significant advances in cellular reprogramming technologies and hematopoietic differentiation from human pluripotent stem cells (hPSCs) have already enabled the routine production of multiple lineages of blood cells in vitro and opened novel opportunities to study hematopoietic development, model genetic blood diseases, and manufacture immunologically matched cells for transfusion and cancer immunotherapy. However, the generation of hematopoietic cells with robust and sustained multilineage engraftment has not been achieved. Here, we highlight the recent advances in understanding the molecular and cellular pathways leading to blood development from hPSCs and discuss potential approaches that can be taken to facilitate the development of technologies for de novo production of hematopoietic stem cells.

scholarly journals Steel factor coordinately regulates the molecular signature and biologic function of hematopoietic stem cells

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 560-567 ◽  
Author(s):  
David G. Kent ◽  
Brad J. Dykstra ◽  
Jay Cheyne ◽  
Elaine Ma ◽  
Connie J. Eaves
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Hematopoietic Stem ◽  
Steel Factor ◽  
Biologic Function

Abstract Hematopoietic stem cells (HSCs) regenerated in vivo display sustained differences in their self-renewal and differentiation activities. Variations in Steel factor (SF) signaling are known to affect these functions in vitro, but the cellular and molecular mechanisms involved are not understood. To address these issues, we evaluated highly purified HSCs maintained in single-cell serum-free cultures containing 20 ng/mL IL-11 plus 1, 10, or 300 ng/mL SF. Under all conditions, more than 99% of the cells traversed a first cell cycle with similar kinetics. After 8 hours in the 10 or 300 ng/mL SF conditions, the frequency of HSCs remained unchanged. However, in the next 8 hours (ie, 6 hours before any cell divided), HSC integrity was sustained only in the 300 ng/mL SF cultures. The cells in these cultures also contained significantly higher levels of Bmi1, Lnk, and Ezh2 transcripts but not of several other regulators. Assessment of 21 first division progeny pairs further showed that only those generated in 300 ng/mL SF cultures contained HSCs and pairs of progeny with similar differentiation programs were not observed. Thus, SF signaling intensity can directly and coordinately alter the transcription factor profile and long-term repopulating ability of quiescent HSCs before their first division.

MSC-Derived HSCs Can Reconstitute Hematopoietic Function In Patients With Severe Aplastic Anemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2432-2432 ◽  
Author(s):  
James Q Yin ◽  
Chunji Gao ◽  
Bing Han ◽  
Jianliang Sheng
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Aplastic Anemia ◽  
Blood Cells ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Severe Aplastic Anemia ◽  
Hematopoietic Stem

Abstract Introduction Naturally-occurring regeneration of cells and tissues is generally involved in four working mechanisms such as directed differentiation, dedifferentiation, trans-differentiation and transdetermination. The better exploring of these mechanisms could be beneficial to develop clinical strategies for regenerative medicine and to reduce the likelihood of immune rejection and relevant complications Recently, “trans-determination” has attracted great controversy, mostly in regards to whether adult stem cells can colonize other tissues after transplantation. More importantly, how to generate large amounts of a particular stem cell type through a transdetermination process remained to be unsolved. Similarly, it is unclear whether mesenchymal stem cells (MSCs) can transdeterminate into hematopoietic stem cells (HSCs). Methods Many technologies were used to validate the transdetermination of adipose-derived mesenchymal stem cells (AD-MSCs) into hematopoietic stem cells (HSCs) from different aspects. They include FACS analysis, PCR tests, immunostaining, expansion and repopulating assays, transplantation analysis and others, showing their in vivo and in vitro potentials for long-term self-renewal and differentiation into multi-lineages of blood cells. Moreover, these AD-HSCs can reconstitute hematopoietic function in six patients. Results We report firstly here that a huge number of human AD-MSCs that are CD44+,CD29+, CD105+, CD166+,CD133-,CD34- could rapidly transdifferentiate into hematopoietic stem cells (CD49f+/CD133+/CD34+) and their descending blood cells in vitro, after transfected with two small RNAs. The sRNAs were high-effectively delivered into MSCs by a novel peptide means. These adipose-derived HSCs (AD-HSCs) could form different types of hematopoietic colonies as nature-occurring HSCs did. Upon the primary and secondary transplantation into sublethally or lethally irradiated mice, these MSC-HSCs engrafted and differentiated into all hematopoietic lineages such as erythrocytes, lymphocytes, myelocytes and thrombocytes. Furthermore, we demonstrated the first evidence that the transdetermination of MSCs was induced by acetylation of histone proteins and activation of many transcriptional factors. More excitingly, these MSC-derived HSCs can reconstitute hematopoietic function in six patients with severe aplastic anemia. Conclusion our findings identify the molecular mechanisms that regulate the directed transdifferentiation of MSCs toward HSCs, create a new source for individual HSC transplantation used for the treatment of blood diseases and cancers, and break the stalemate caused by bone marrow match and graft-versus-host disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis

2005 ◽  
Vol 202 (1) ◽  
pp. 169-179 ◽  
Author(s):  
Yuko Kato ◽  
Atsushi Iwama ◽  
Yuko Tadokoro ◽  
Kazuya Shimoda ◽  
Mayu Minoguchi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Leukemic Stem Cells ◽  
Myeloproliferative Disease ◽  
Self Renewal ◽  
Hematopoietic Stem

Although the concept of a leukemic stem cell system has recently been well accepted, its nature and the underlying molecular mechanisms remain obscure. Constitutive activation of signal transducers and activators of transcription 3 (STAT3) and STAT5 is frequently detected in various hematopoietic tumors. To evaluate their role in normal and leukemic stem cells, we took advantage of constitutively active STAT mutants to activate STAT signaling selectively in hematopoietic stem cells (HSCs). Activation of STAT5 in CD34–c-Kit+Sca-1+ lineage marker– (CD34–KSL) HSCs led to a drastic expansion of multipotential progenitors and promoted HSC self-renewal ex vivo. In sharp contrast, STAT3 was demonstrated to be dispensable for the HSC maintenance in vivo, and its activation facilitated lineage commitment of HSCs in vitro. In a mouse model of myeloproliferative disease (MPD), sustained STAT5 activation in CD34–KSL HSCs but not in CD34+KSL multipotential progenitors induced fatal MPD, indicating that the capacity of STAT5 to promote self-renewal of hematopoietic stem cells is crucial to MPD development. Our findings collectively establish a specific role for STAT5 in self-renewal of normal as well as leukemic stem cells.

scholarly journals Blood making: learning what to put into the dish

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 38 ◽  
Author(s):  
Ana G Freire ◽  
Jason M Butler
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Pluripotent Stem Cell ◽  
Current Knowledge ◽  
Comprehensive Understanding ◽  
Hematopoietic Stem ◽  
Hematopoietic Development ◽  
Cellular Factors ◽  
Bona Fide

The generation of hematopoietic stem cells (HSCs) from pluripotent stem cell (PSC) sources is a long-standing goal that will require a comprehensive understanding of the molecular and cellular factors that determine HSC fate during embryogenesis. A precise interplay between niche components, such as the vascular, mesenchymal, primitive myeloid cells, and the nervous system provides the unique signaling milieu for the emergence of functional HSCs in the aorta-gonad-mesonephros (AGM) region. Over the last several years, the interrogation of these aspects in the embryo model and in the PSC differentiation system has provided valuable knowledge that will continue educating the design of more efficient protocols to enable the differentiation of PSCs into bona fide, functionally transplantable HSCs. Herein, we provide a synopsis of early hematopoietic development, with particular focus on the recent discoveries and remaining questions concerning AGM hematopoiesis. Moreover, we acknowledge the recent advances towards the generation of HSCs in vitro and discuss possible approaches to achieve this goal in light of the current knowledge.

scholarly journals Essential Role of Endogenous MOZ in Aberrant HoxA9 and Meis1 Expressions Induced By MOZ Fusion Gene

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2191-2191
Author(s):  
Takuo Katsumoto ◽  
Kazutsune Yamagata ◽  
Yoko Ogawara ◽  
Takuro Nakamura ◽  
Issay Kitabayashi
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Molecular Mechanisms ◽  
Zinc Finger Protein ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Leukemia Cells ◽  
Hematopoietic Stem

Abstract Monocytic leukemia Zinc finger protein (MOZ), a histone acetyltransferase, is involved in chromosome translocations associated with FAB M4/M5 types of acute myeloid leukemia (AML). In normal hematopoiesis, MOZ is essential for self-renewal of hematopoietic stem cells (HSCs) and for expression of HoxA9/Meis1 in hematopoietic stem/progenitor cells (HSPCs). Previously we found that endogenous MOZ is critical for MOZ-TIF2-induced AML. Although MOZ-/- cells expressing the MOZ-fusion serially generated colonies in vitro, they did not induce AML after transplantation into recipient mice. In these cells, up-regulation of Meis1 was impaired, while HoxA9 expression was induced. However, roles of endogenous MOZ in MOZ fusion induced leukemia remained unclear. To elucidate molecular mechanisms, we performed experiments described below. First, to reveal mechanisms in defect of Meis1 expression in MOZ-/- MOZ-fusion leukemia cells, we performed chromatin immune-precipitation assays on Meis1 locus. Coincident with gene expression, active histone marks (H3K9ac, H3K27ac etc.) were disrupted. In contrast, repressive histone modifications (H3K9me2, H3K27me3) were elevated. Next we analyzed requirement of HoxA9 and Meis1 in MOZ fusion induced AML development. When mice were transplanted with MOZ-/- HSPCs simultaneously introduced with MOZ-fusion and Meis1 genes, AML development were induced. On the other hand, when Meis1 was conditionally deleted in MOZ-fusion leukemia cells, AML development was significantly delayed. Mice transplanted with MOZ-/- HSPCs, which were introduced with both HoxA9 and Meis1 genes elicited AML development. Furthermore, we analyzed gene expression profiles of MOZ-/- MOZ fusion leukemia cells. In these cells, expressions of monocyte/macrophage lineage characteristic genes (C/EBPa, Irf8, CD68 etc.) and MLL fusion target genes (Meis1, Mef2c) were decreased. In contract, other hematopoietic lineage characteristic genes (GATA1-3, FOG-1, CD41, Aiolos, Helios, Eag, Epx etc.) were increased. In addition, expression of CDK inhibitor INK4A was also up-regulated. Finally, we tested requirement of endogenous MOZ in various cellular conditions. Previous report showed that AML development was induced by introduction of MOZ-TIF2 not only in hematopoietic stem cells but also in more differentiated Common myeloid progenitors (CMPs) and Granulocyte/Monocyte progenitors (GMPs) (Huntly et al, Cancer Cell 2004). So we introduced MOZ fusion genes in HSCs and CMPs collected from E14.5 MOZ-/- fetal liver. MOZ-/- HSCs, not CMPs, expressing MOZ-TIF2 continuously formed colonies in vitro. In the CMPs expressing MOZ-TIF2, expression of both Meis1 and HoxA9, were abolished. These results suggest that high levels of HoxA9 and Meis1 expressions were respectively required for MOZ-TIF2-induced AML development, and that endogenous MOZ is critical for MOZ-TIF2-induced AML development. Disclosures No relevant conflicts of interest to declare.

Strategies to Protect Hematopoietic Stem Cells from Culture-Induced Stress Conditions

2020 ◽  
Vol 15 ◽  
Author(s):  
Fatima Aerts-Kaya
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Ex Vivo ◽  
Stress Conditions ◽  
Stress Factors ◽  
Hematopoietic Stem ◽  
Induced Stress

: In contrast to their almost unlimited potential for expansion in vivo and despite years of dedicated research and optimization of expansion protocols, the expansion of Hematopoietic Stem Cells (HSCs) in vitro remains remarkably limited. Increased understanding of the mechanisms that are involved in maintenance, expansion and differentiation of HSCs will enable the development of better protocols for expansion of HSCs. This will allow procurement of HSCs with long-term engraftment potential and a better understanding of the effects of the external influences in and on the hematopoietic niche that may affect HSC function. During collection and culture of HSCs, the cells are exposed to suboptimal conditions that may induce different levels of stress and ultimately affect their self-renewal, differentiation and long-term engraftment potential. Some of these stress factors include normoxia, oxidative stress, extra-physiologic oxygen shock/stress (EPHOSS), endoplasmic reticulum (ER) stress, replicative stress, and stress related to DNA damage. Coping with these stress factors may help reduce the negative effects of cell culture on HSC potential, provide a better understanding of the true impact of certain treatments in the absence of confounding stress factors. This may facilitate the development of better ex vivo expansion protocols of HSCs with long-term engraftment potential without induction of stem cell exhaustion by cellular senescence or loss of cell viability. This review summarizes some of available strategies that may be used to protect HSCs from culture-induced stress conditions.

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