scholarly journals FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2149
Author(s):  
Zhi Feng ◽  
Chenyu Lin ◽  
Limei Tu ◽  
Ming Su ◽  
Chunyu Song ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Ex Vivo ◽  
Cord Blood Transplantation ◽  
Drug Repurposing ◽  
Suitable Model ◽  
Dependent Manner ◽  
Blood Disorders ◽  
Hematopoietic Stem ◽  
Blood Transplantation ◽  
Stem And Progenitor Cells

Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs’ administration caused HSPCs diminishment and 118 drugs’ treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1−/− mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.

scholarly journals Ex vivo expansion of human hematopoietic stem and progenitor cells

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6083-6090 ◽  
Author(s):  
Ann Dahlberg ◽  
Colleen Delaney ◽  
Irwin D. Bernstein
Keyword(s):  
Stem Cell ◽  
Growth Factors ◽  
Notch Signaling ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Hematopoietic Growth Factors ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

AbstractDespite progress in our understanding of the growth factors that support the progressive maturation of the various cell lineages of the hematopoietic system, less is known about factors that govern the self-renewal of hematopoietic stem and progenitor cells (HSPCs), and our ability to expand human HSPC numbers ex vivo remains limited. Interest in stem cell expansion has been heightened by the increasing importance of HSCs in the treatment of both malignant and nonmalignant diseases, as well as their use in gene therapy. To date, most attempts to ex vivo expand HSPCs have used hematopoietic growth factors but have not achieved clinically relevant effects. More recent approaches, including our studies in which activation of the Notch signaling pathway has enabled a clinically relevant ex vivo expansion of HSPCs, have led to renewed interest in this arena. Here we briefly review early attempts at ex vivo expansion by cytokine stimulation followed by an examination of our studies investigating the role of Notch signaling in HSPC self-renewal. We will also review other recently developed approaches for ex vivo expansion, primarily focused on the more extensively studied cord blood–derived stem cell. Finally, we discuss some of the challenges still facing this field.

scholarly journals Dectin-1 Stimulation of Hematopoietic Stem and Progenitor Cells Occurs In Vivo and Promotes Differentiation Toward Trained Macrophages via an Indirect Cell-Autonomous Mechanism

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Cristina Bono ◽  
Alba Martínez ◽  
Javier Megías ◽  
Daniel Gozalbo ◽  
Alberto Yáñez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Candida Albicans ◽  
Progenitor Cells ◽  
Recipient Mouse ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Hematopoietic Stem ◽  
Content Type ◽  
Stem And Progenitor Cells

ABSTRACT Toll-like receptor (TLR) agonists drive hematopoietic stem and progenitor cells (HSPCs) to differentiate along the myeloid lineage. In this study, we used an HSPC transplantation model to investigate the possible direct interaction of β-glucan and its receptor (dectin-1) on HSPCs in vivo. Purified HSPCs from bone marrow of B6Ly5.1 mice (CD45.1 alloantigen) were transplanted into dectin-1−/− mice (CD45.2 alloantigen), which were then injected with β-glucan (depleted zymosan). As recipient mouse cells do not recognize the dectin-1 agonist injected, interference by soluble mediators secreted by recipient cells is negligible. Transplanted HSPCs differentiated into macrophages in response to depleted zymosan in the spleens and bone marrow of recipient mice. Functionally, macrophages derived from HSPCs exposed to depleted zymosan in vivo produced higher levels of inflammatory cytokines (tumor necrosis factor alpha [TNF-α] and interleukin 6 [IL-6]). These results demonstrate that trained immune responses, already described for monocytes and macrophages, also take place in HSPCs. Using a similar in vivo model of HSPC transplantation, we demonstrated that inactivated yeasts of Candida albicans induce differentiation of HSPCs through a dectin-1- and MyD88-dependent pathway. Soluble factors produced following exposure of HSPCs to dectin-1 agonists acted in a paracrine manner to induce myeloid differentiation and to influence the function of macrophages derived from dectin-1-unresponsive or β-glucan-unexposed HSPCs. Finally, we demonstrated that an in vitro transient exposure of HSPCs to live C. albicans cells, prior to differentiation, is sufficient to induce a trained phenotype of the macrophages they produce in a dectin-1- and Toll-like receptor 2 (TLR2)-dependent manner. IMPORTANCE Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections. Understanding host defense is essential to design novel therapeutic strategies to boost immune protection against Candida albicans. In this article, we delve into two new concepts that have arisen over the last years: (i) the delivery of myelopoiesis-inducing signals by microbial components directly sensed by hematopoietic stem and progenitor cells (HSPCs) and (ii) the concept of “trained innate immunity” that may also apply to HSPCs. We demonstrate that dectin-1 ligation in vivo activates HSPCs and induces their differentiation to trained macrophages by a cell-autonomous indirect mechanism. This points to new mechanisms by which pathogen detection by HSPCs may modulate hematopoiesis in real time to generate myeloid cells better prepared to deal with the infection. Manipulation of this process may help to boost the innate immune response during candidiasis.

Adhesion to Fibronectin Maintains Regenerative Capacity During Ex Vivo Culture and Transduction of Human Hematopoietic Stem and Progenitor Cells

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4612-4621 ◽  
Author(s):  
M.A. Dao ◽  
K. Hashino ◽  
I. Kato ◽  
J.A. Nolta
Keyword(s):  
Progenitor Cells ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Retroviral Vectors ◽  
Current Data ◽  
Regenerative Capacity ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Ex Vivo Culture

Abstract Recent reports have indicated that there is poor engraftment from hematopoietic stem cells (HSC) that have traversed cell cycle ex vivo. However, inducing cells to cycle in culture is critical to the fields of ex vivo stem cell expansion and retroviral-mediated gene therapy. Through the use of a xenograft model, the current data shows that human hematopoietic stem and progenitor cells can traverse M phase ex vivo, integrate retroviral vectors, engraft, and sustain long-term hematopoiesis only if they have had the opportunity to engage their integrin receptors to fibronectin during the culture period. If cultured in suspension under the same conditions, transduction is undetectable and the long-term multilineage regenerative capacity of the primitive cells is severely diminished.

Clinical-scale validation of a new efficient procedure for cryopreservation of ex vivo expanded cord blood hematopoietic stem and progenitor cells

Cytotherapy ◽  
2016 ◽  
Vol 18 (12) ◽  
pp. 1543-1547 ◽  
Author(s):  
Pascale Duchez ◽  
Laura Rodriguez ◽  
Jean Chevaleyre ◽  
Philippe Brunet De La Grange ◽  
Zoran Ivanovic
Keyword(s):  
Cord Blood ◽  
Progenitor Cells ◽  
Scale Validation ◽  
Ex Vivo ◽  
Clinical Scale ◽  
Hematopoietic Stem ◽  
Efficient Procedure ◽  
Stem And Progenitor Cells

scholarly journals EFFECTS OF N-ACETYL-CYSTEINE SUPPLEMENTATION ON EX-VIVO CLONOGENICITY AND OXIDATIVE PROFILE OF LINEAGE-COMMITTED HEMATOPOIETIC STEM/PROGENITOR CELLS

2018 ◽  
Vol 80 (3) ◽  
Author(s):  
Chan Chin Yi ◽  
Zariyantey Abd Hamid ◽  
Izatus Shima Taib ◽  
Tan Hui Yee ◽  
Muhd Khairul Akmal Wak Harto ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Ex Vivo ◽  
Oxidative Status ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
Colony Forming Units ◽  
Stem And Progenitor Cells ◽  
Acetyl Cysteine ◽  
Antioxidant Supplement ◽  
B Lymphoid

Hematopoietic stem and progenitor cells (HSPCs) are exposed to oxidative damage acquired during ex vivo expansion which affects their therapeutic potency. Efforts to overcome this limitation includes the use of antioxidants. The effects of N-Acetyl-Cysteine (NAC) supplementation for 48 hours on maintenance of ex vivo HSPCs was investigated by examining the cell viability at concentrations of 0.125 µM, 0.25 µM, 0.5 µM, 1.0 µM and 2.0 µM, followed by clonogenicity and oxidative status assessments of lineage-committed progenitors (myeloid, erythroid and pre-B lymphoid) at selected NAC concentrations (0.25 µM, 0.5 µM, 2.0 µM). NAC supplementation significantly (p< 0.05) enhanced viability of HSPC at 0.25 µM, 0.5 µM, 2.0 µM.  The clonogenicity of each progenitor was not affected as no significant changes of Colony Forming Units (CFUs) counts was noted between NAC-supplemented group than control. NAC showed no significant effects on reactive oxygen species (ROS), glutathione (GSH) and superoxide dismutase (SOD) levels of respective progenitors as compared to control. Conclusively, NAC shows potential property as antioxidant supplement for ex vivo maintenance of HSPCs by promoting survivability and maintaining clonogenicity.

scholarly journals Directed Differentiation of Mobilized Hematopoietic Stem and Progenitor Cells into Functional NK Cells with Enhanced Antitumor Activity

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 811
Author(s):  
Pranav Oberoi ◽  
Kathrina Kamenjarin ◽  
Jose Francisco Villena Ossa ◽  
Barbara Uherek ◽  
Halvard Bönig ◽  
...  
Keyword(s):  
Nk Cells ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Cell Expansion ◽  
Nk Cell ◽  
Ex Vivo ◽  
Feeder Cells ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Stem And Progenitor Cells

Obtaining sufficient numbers of functional natural killer (NK) cells is crucial for the success of NK-cell-based adoptive immunotherapies. While expansion from peripheral blood (PB) is the current method of choice, ex vivo generation of NK cells from hematopoietic stem and progenitor cells (HSCs) may constitute an attractive alternative. Thereby, HSCs mobilized into peripheral blood (PB-CD34+) represent a valuable starting material, but the rather poor and donor-dependent differentiation of isolated PB-CD34+ cells into NK cells observed in earlier studies still represents a major hurdle. Here, we report a refined approach based on ex vivo culture of PB-CD34+ cells with optimized cytokine cocktails that reliably generates functionally mature NK cells, as assessed by analyzing NK-cell-associated surface markers and cytotoxicity. To further enhance NK cell expansion, we generated K562 feeder cells co-expressing 4-1BB ligand and membrane-anchored IL-15 and IL-21. Co-culture of PB-derived NK cells and NK cells that were ex-vivo-differentiated from HSCs with these feeder cells dramatically improved NK cell expansion, and fully compensated for donor-to-donor variability observed during only cytokine-based propagation. Our findings suggest mobilized PB-CD34+ cells expanded and differentiated according to this two-step protocol as a promising source for the generation of allogeneic NK cells for adoptive cancer immunotherapy.

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