The OCIAD protein family: comparative developmental biology and stem cell application

2020 ◽  
Vol 64 (1-2-3) ◽  
pp. 213-225
Author(s):  
Wulligundam Praveen ◽  
Saloni Sinha ◽  
Rajarshi Batabyal ◽  
Kajal Kamat ◽  
Maneesha S. Inamdar
Keyword(s):  
Stem Cells ◽  
Developmental Biology ◽  
Stem Cell ◽  
Information Overload ◽  
Ex Vivo ◽  
Developmental Models ◽  
Clinically Significant ◽  
Insight Into ◽  
Compare Analysis

Over the last two decades, an exponential growth in technologies and techniques available to biologists has provided mind-boggling quantities of data and led to information overload. Yet, answers to fundamental questions such as “how are we made?” and “what keeps us ticking?” remain incomplete. Developmental biology has provided elegant approaches to address such questions leading to enlightening insights. While several important contributions to developmental biology have come from India over the decades, this area of research remains nascent. Here, we review the journey in India, from the discovery of the ociad gene family to decoding its role in development and stem cells. We compare analysis in silico, in vivo and ex vivo, with developmental models such as Drosophila, mouse and stem cells that gave important insight into how these clinically significant genes function.

Ex-Vivo Expansion of Multipotent CD133+ Stem Cells with VEGF, FLT3l and SCGF.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4147-4147
Author(s):  
Sonja Loges ◽  
Martin Butzal ◽  
Uta Fischer ◽  
Ursula M. Gehling ◽  
Dieter K. Hossfeld ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Stem Cell ◽  
Culture System ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Facs Analysis ◽  
Hematopoietic Stem ◽  
Large Numbers

Abstract The rare CD133+ stem cell population contains both hematopoietic and endothelial progenitors. Successful ex-vivo expansion of this multipotent population would therefore be of great benefit in many clinical settings including stem cell transplantation and gene therapy. We developed a cell culture system containing the recombinant human cytokines vascular endothelial growth factor (VEGF), FLT3 ligand (FLT3L) and stem cell growth factor (SCGF) for ex-vivo expansion of purified human CD133+ stem cells obtained from leukapheresis products from patients pre-treated with G-CSF. FACS analysis, colony assays and NOD-SCID transplantation studies were performed to monitor stem cell and endothelial phenotype in-vitro and in-vivo. Cultivation with VEGF, FLT3L and SCGF induced a mean 2200-fold increase of total cell counts in 5 weeks. FACS analysis revealed persistence of 6–15% CD133+ stem cells indicating proliferation and survival of primitive hematopoietic stem cells. 5–6% of the proliferating cells expressed the endothelial markers CD144 (VE-Cadherin) and von-Willebrand factor (vWF). Ex-vivo expanded stem cells could be differentiated into adherent endothelial cells after withdrawal of SCGF and FLT3L allowing generation of large numbers of endothelial cells. Colony-assays showed an increase of hematopoietic and endothelial colonies after 5 weeks of ex-vivo expansion indicating simultaneous proliferation of hematopoietic and endothelial precursors under the established culture conditions (CFU-E 60-fold, CFU-GEMM 48-fold, CFU-GM 59-fold, CFU-G 99-fold, CFU-M 1356-fold and CFU-EC 1843-fold). To assess in-vivo functionality, hematopoietic stem cells expanded ex-vivo for 7, 14, 21 and 32 days were transplanted into sublethally irradiated NOD-SCID mice. For each expansion period, the mean percentage of anti-human CD45 positive bone marrow cells 3 months post-transplantation was 11, 3, 3 and 1%, respectively. Human CD45+ cells for each set of experiments contained a mean of 15, 26, 8 and 32% T-cells (CD3+), 9, 0, 7 and 21% B-cells (CD19+), 24, 2, 2 and 11% monocytes (CD14+), 21, 3, 1 and 12% granulocytes (CD33+) and 19, 37, 44 and 24% stem cells (CD34+) (d7 (n=5), d14 (n=4), d21 (n=7) and d32 (n=6) respectively). Our experiments showed multilineage engraftment of human stem cells expanded for more than 4 weeks ex-vivo. Therefore our culture system provides a tool to generate large numbers of human stem and endothelial cells for clinical purposes.

Comparative Blood Group Profiling of Human Erythroid Cells (EBs) Generated from Adult Blood (AB), Cord Blood (CB), Human Embryonic Stem Cells (hESC) and Induced Pluripotent Stem Cells (iPS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1027-1027 ◽  
Author(s):  
Barbara Ghinassi ◽  
Maria Themeli ◽  
Kai-Hsin Chang ◽  
Gregory Halverson ◽  
Ghazala Hashmi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Blood Group ◽  
Ex Vivo ◽  
Antigen Expression ◽  
Band 3 ◽  
Blood Group Antigens ◽  
Dna Genotyping

Abstract Abstract 1027 Red blood cells (RBC) survive shear forces in the microvasculature because trans-membrane complexes embedded in the lipid bilayer attach their membrane to the cytoskeleton assuring its flexibility. The expression of clinically relevant red blood cell antigens present on these complexes is determined by genetic polymorphisms and their developmental regulation. Therefore, flow cytometry studies of blood group antigens may provide insights both on potential immunogenicity and on membrane structure of ex-vivo generated EBs. Blood group antigen profiles of EBs expanded ex vivo from one AB (three experiments), three CB, the H1 hESC line and one iPS line derived from mononuclear cells from a healthy donor were compared by flow cytometry using commercially available antibodies recognizing antigens present on proteins in the 4.1R [Duffy (Fya and Fy3), Kell (Kell prot, K/k, Kpa/Kpb, Jsb) and glycophorin C (GPC, Ge2)] and ankyrin R [glycophorin A (GPA, CD235a, M and EnaFS) RhAG and band 3 (Wrb)] complexes and on other important membrane proteins [glycophorin B (GPB, s and U), urea transporter (Kidd, Jk3), the complement receptor (CD35) and inhibitors of complement-mediated lysis (CD55 and CD59)]. Controls included DNA genotyping (CB, AB and H1-hESC) (HEA-Bead Chip, Immunocor, Norcross, GA) and immunophenotyping of blood red cells from the same AB and CB. Antigen expression similar to that observed on in vivo generated RBC was considered normal. EBs were generated from AB and CB at day 10 in HEMAser cultures whereas EBs from hESC and iPS were derived using previously optimized protocols. The maturation state was determined by morphological analyses and CD36/CD235a profiles. Irrespective of the stem cell source, the immunophenotype of ex-vivo expanded EBs was consistent with that predicted by genotyping. However, source specific differences in the magnitude of antigen expression and in the changes with maturation were observed (see Figure). Immature EBs from AB expressed normal levels of the antigens present on both the 4.1R (Duffy, Kell, GPC) and ankyrin R (GPA, M/N, EnaFS, RhAG and band 3) complexes. With maturation, expression of 4.1R-associated antigens remained normal while that of ankyrin R associated antigens varied (M decreased and RhAG increased). EBs from CB expressed normal levels of antigens present on the ankyrin R complex and of some of those present on the 4.1R complex (Duffy, Kell protein and GPA). However, expression of epitopes on Kell protein varied with some antigens expressed at normal levels (k and Jsb) and others (Kpa/Kpb) at levels 2x greater than normal. With maturation, CB-derived EBs maintained normal levels of ankyrin R associated antigens while those associated with complex 4.1R became barely detectable. EB from hESC expressed unbalanced levels of proteins associated with both ankyrin R (2x levels of GPA and barely detectable levels of RhAG) and 4.1R [3x levels of Duffy and 2x levels of Jsb (Kell) with normal levels of k and Kpb (Kell) antigens] complexes. The variegation in expression of different epitopes on the same protein observed with CB- and hESC-derived EBs likely reflect altered structural conformation of the complexes rather than differences in protein concentration on the membrane. EBs from iPS, as those from AB, expressed normal levels of antigens present on Ankyrin R and 4.1R complexes which increased with maturation. Irrespective of stem cell sources, EBs expressed normal levels of GPB and Kidd. EBs from AB expressed normal levels of the complement regulatory proteins tested which in the case of CD59 CD59 decreased with maturation. EBs from CB expressed normal levels of CD35 and CD59 but 2x levels of CD55 with expression of CD35 and CD55 decreasing with maturation. EBs from iPS expressed 2x levels of CD35 and CD55 and expression of these antigens was not affected by maturation. The observation that blood group antigenic profiles of ex-vivo generated EBs are consistent with those predicted by DNA-genotyping suggests that these cells are unlikely to be immunogenic for known epitopes. However, the antigen profiles of ankyrin R and 4.1R complexes were normal only for AB and iPS-derived EBs raising the possibility that antigenic deviations seen in EBs derived from CB and hESC may have immunologic or functional consequences in vivo. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Stem cells and lung regeneration

2020 ◽  
Vol 319 (4) ◽  
pp. C675-C693
Author(s):  
Kalpaj R. Parekh ◽  
Janna Nawroth ◽  
Albert Pai ◽  
Shana M. Busch ◽  
Christiana N. Senger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Lung Disease ◽  
Progenitor Cell ◽  
Human Lung ◽  
Ex Vivo ◽  
Cell Types ◽  
And Function ◽  
Lung Regeneration

The ability to replace defective cells in an airway with cells that can engraft, integrate, and restore a functional epithelium could potentially cure a number of lung diseases. Progress toward the development of strategies to regenerate the adult lung by either in vivo or ex vivo targeting of endogenous stem cells or pluripotent stem cell derivatives is limited by our fundamental lack of understanding of the mechanisms controlling human lung development, the precise identity and function of human lung stem and progenitor cell types, and the genetic and epigenetic control of human lung fate. In this review, we intend to discuss the known stem/progenitor cell populations, their relative differences between rodents and humans, their roles in chronic lung disease, and their therapeutic prospects. Additionally, we highlight the recent breakthroughs that have increased our understanding of these cell types. These advancements include novel lineage-traced animal models and single-cell RNA sequencing of human airway cells, which have provided critical information on the stem cell subtypes, transition states, identifying cell markers, and intricate pathways that commit a stem cell to differentiate or to maintain plasticity. As our capacity to model the human lung evolves, so will our understanding of lung regeneration and our ability to target endogenous stem cells as a therapeutic approach for lung disease.

Reducing Stem Cell Loss and Ex Vivo Differentiation during Lentivirus Gene Transfer to Murine Stem Cells - an Ultra-Short Transduction Protocol.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2113-2113
Author(s):  
Peter Kurre ◽  
Ponni Anandakumar ◽  
Vladimir A. Lesnikov ◽  
Hans-Peter Kiem
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Gene Transfer ◽  
Ex Vivo ◽  
Lentivirus Vectors ◽  
Ex Vivo Culture ◽  
Marrow Cells

Abstract Most gene transfer models using Moloney murine leukemia virus (MLV) - derived vectors to target hematopoietic repopulating cells require progenitor cell enrichment and extended ex vivo culture for efficient long-term marking. Both may result in qualitative, and/or quantitative, loss of stem cells thereby limiting gene transfer rates in vivo. This can be a critical obstacle in candidate applications with exhausted autologous stem cell pools, such as Fanconi Anemia. Among the advantages of HIV-derived lentivirus vectors is their ability to transduce non dividing cells, permitting shortened ex vivo culture durations while maintaining gene transfer to long-term repopulating cells. We have previously reported long-term gene transfer rates of 12–40% after VSV-G/ lentivirus vector transduction of murine stem cells by targeting unseparated marrow cells after reduced prestimulation and a single 12 hour vector exposure (Kurre et al., Mol. Ther. 2004 Jun;9(6):914–22). We herein report studies showing maintenance of gene transfer efficiency in this model at drastically reduced ex vivo vector exposure times. In initial in vitro experiments we studied cytokine support, vector particle density, and minimum exposure duration requirements for efficient gene transfer to unseparated marrow cells. We determined that fibronectin fragment support was critical in maintaining minimum gene transfer efficiencies, even during brief 1, or 3-hour exposures. In an effort to extend these in vitro findings targeting a mixed leukocyte population and explore the feasibility in vivo, we next performed repopulation experiments in myeloablated murine recipients. Unseparated marrow cells harvested from donor animals were depleted of red blood cells, washed and immediately transduced on fibronectin fragment in the presence of murine stem cell factor. Following a 1 hour exposure to lentivector (VSV-G/RRLsin-cPPThPGK-EGFPwpre), cells were washed repeatedly, resuspended and injected into myeloablated recipients (n=10). Animals showed ready hematopoietic reconstitution and demonstrated average GFP marking of 31% (range: 17–41.2%) in peripheral blood 20 weeks after transplantation. Gene marking in secondary recipients 9 weeks after reconstitution (n=15, 3 recipient animals per donor) persisted at 29% on average (range 14.9–66%). Results also demonstrate transduction of granulocytes, B- and T-lymphocytes, as well as stable long-term GFP expression in primary and secondary animals. Copy number determination by real-time PCR in marrow cells from primary recipients shows an average of 4 proviral copies (range 2.1–8.1) per GFP-expressing cell. Our studies confirm that HIV-derived lentivirus vectors are ideally suited for the transduction of murine long-term repopulating cells. We hypothesize that ultra-short transduction actively preserves stem cell content in the inoculum. Moreover, this protocol represents an ideal platform for subsequent in vivo selection to achieve complete phenotype correction and high-level therapeutic chimerism required for some applications. We anticipate that our strategy may prove particularly useful in situations where the target stem cell quantity is greatly limited and cells are of poor ex vivo viability.

scholarly journals Neural stem cell temporal patterning and brain tumour growth rely on oxidative phosphorylation

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jelle van den Ameele ◽  
Andrea H Brand
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Oxidative Phosphorylation ◽  
Tumour Cells ◽  
Neuronal Diversity ◽  
Temporal Patterning ◽  
Cell Behaviour ◽  
Drosophila Brain ◽  
Insight Into

Translating advances in cancer research to clinical applications requires better insight into the metabolism of normal cells and tumour cells in vivo. Much effort has focused on understanding how glycolysis and oxidative phosphorylation (OxPhos) support proliferation, while their impact on other aspects of development and tumourigenesis remain largely unexplored. We found that inhibition of OxPhos in neural stem cells (NSCs) or tumours in the Drosophila brain not only decreases proliferation, but also affects many different aspects of stem cell behaviour. In NSCs, OxPhos dysfunction leads to a protracted G1/S-phase and results in delayed temporal patterning and reduced neuronal diversity. As a consequence, NSCs fail to undergo terminal differentiation, leading to prolonged neurogenesis into adulthood. Similarly, in brain tumours inhibition of OxPhos slows proliferation and prevents differentiation, resulting in reduced tumour heterogeneity. Thus, in vivo, highly proliferative stem cells and tumour cells require OxPhos for efficient growth and generation of diversity.

scholarly journals A switch in cilia-mediated Hedgehog signaling controls muscle stem cell quiescence and cell cycle progression

2019 ◽  
Author(s):  
Sara Betania Cruz-Migoni ◽  
Kamalliawati Mohd Imran ◽  
Aysha Wahid ◽  
Oisharja Rahman ◽  
James Briscoe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Ex Vivo ◽  
List Type ◽  
Quiescent State ◽  
Self Renewal ◽  
Cycle Progression

SummaryTissue homeostasis requires a tight control of stem cells to maintain quiescence in normal conditions, and ensure a balance between progenitor cell production and the need to preserve a stem cell pool in repair conditions. Using ex-vivo and in-vivo genetic approaches, we provide evidence that primary cilium-mediated repressive Hedgehog (Hh) signalling is required to maintain skeletal muscle stem cells (MuSCs) in a quiescent state. De-repression and further activation of Hh signalling initiates MuSC entry and progression through the cell cycle, and controls self-renewal to ensure efficient repair of injured muscles. We propose a model whereby disassembly of primary cilia upon MuSC activation induces a switch in Hh signalling from a repressive to active state that controls exit from quiescence. Positive Hh response in bi-potential muscle progenitor cells regulates also cell cycle progression and drives MuSC self-renewal. These findings identify Hh signalling as a major regulator of MuSC activity.HighlightsCilia-containing quiescent MuSCs are Hh signalling suppressedMuSC activation coincides with a switch to active Hh signallingSmo mutation delays cell cycle entry and progression, and causes impaired self-renewalPtch1 mutation promotes exit from quiescence, rapid cell cycle and increased self-renewalGraphical abstract

scholarly journals Ex vivo Engineering of Platelets

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-6-SCI-6 ◽  
Author(s):  
Koji Eto
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Nk Cells ◽  
Platelet Transfusion ◽  
Ex Vivo ◽  
Induced Pluripotent Stem Cell ◽  
Human Platelets ◽  
Induced Pluripotent ◽  
Cell Stem Cell

Platelet transfusion is necessary for patients in thrombocytopenic states. Due to short shelf life of platelet product, the shortage of blood donors in the younger population as the consequence of aging societies in developed countries and platelet transfusion refractoriness (PTR) caused by alloimmune response, the risk of platelet product shortage has been a concern. Therefore, many attempts to substitute donor-dependent platelet product have been proposed. Induced pluripotent stem cell (iPSC) derived-platelet like particle product (which we refer as iPS-platelets) is aimed to provide measures against alloimmune PTR as well as to complement the current blood donor-dependent system.To generate the huge number of platelets required for transfusion into thrombocytopenia patients (200-300 billion per transfusion) ex vivo, megakaryopoiesis and subsequent platelet biogenesis process from megakaryocytes needed to be both substantially elucidated in mechanical systems. For the former, our key measure is to expand the immortalized megakaryocyte cell lines (imMKCLs) derived from iPSCs, whereby c-MYC, BMI-1, and Bcl-XL are overexpressed under doxycycline-inducible system to regulate proliferation of megakaryocyte progenitors (Cell Stem Cell, 2014). For the latter, in vivovisualization of mouse bone marrow revealed the presence of turbulence adjacent to megakaryocytes actively releasing platelets, which prompted us to utilize a unique turbulent flow-incorporated bioreactor to produce iPS-platelets. Furthermore, we succeeded in identifying turbulent energy and shear stress as essential physical parameters and further determined the optimal values, thereby to enable efficient and intact ex vivoplatelet manufacture, as exemplified by lowered Annexin V binding values in iPS-platelets, comparable with donor-human platelets. Simultaneously, we developed a culture medium cocktail including a thrombopoietin (TPO) mimetic small compound, an ADAM10/17 inhibitor for the maintenance of GPIb-alpha expression on platelets, an arylhydrocarbon receptor inhibitor, and a ROCK inhibitor for feeder cell-independent megakaryocyte maturation (Stem Cells Transl Med, 2017; Blood Adv, 2017; Blood Adv, 2018). By scaling up of the bioreactor, 100 billion iPS-platelets were produced in 8 L scale. In vitro and in vivo evaluation of iPS-platelets showed the functionality comparable with blood donor-derived platelets (Cell, 2018), including the newly developed thrombocytopenia rabbit model (Transfusion, 2017). Meanwhile, an iPS cell-derived human leukocyte antigen (HLA) class-I-null imMKCL as a universal HLA platelet source is potentially the best solution for alloimmune PTR. However, the immunogenic properties are still unclear, especially regarding natural killer (NK) cells that attack HLA-downregulated cells. Therefore, we evaluated the immunological reaction between HLA-null platelets and NK cells by using our newly developed alloimmune PTR in vivo model in which human NK cells are highly reconstituted in MISTRG mice (Suzuki and Sugimoto et al.,manuscript in revision). This pre-clinical study model should provide a proof-of concept for the clinical application of HLA-null iPS-platelets as a universal platelet product for future transfusion. References Nakamura S, et al. Expandable Megakaryocyte Cell Lines Enable Clinically Applicable Generation of Platelets from Human Induced Pluripotent Stem Cells. Cell Stem Cell. 2014, 14, 535-548.Hirata S, et al. Selective Inhibition of ADAM17 Efficiently Mediates Glycoprotein IbαRetention During Ex Vivo Generation of Human Induced Pluripotent Stem Cell-Derived Platelets. Stem Cells Transl Med. 2017, 6, 720-730.Aihara A, et al. Novel TPO receptor agonist TA-316 contributes to platelet biogenesis from human iPS cells. Blood Adv. 2017, 1, 468-476.Seo H, Chen SJ, et al. A β1-tubulin-based megakaryocyte maturation reporter system identifies novel drugs that promote platelet production. Blood Adv. 2018, 2, 2262-2272.Ito Y, Nakamura S, et al. Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production. Cell. 2018, 174, 636-648.Watanabe N, et al. Refined methods to evaluate the in vivo hemostatic function and viability of transfused human platelets in rabbit models. Transfusion. 2017, 57, 2035-2044. Disclosures Eto: Megakaryon Co. Ltd.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Our published results that include some drugs, i.e., TA-316 (Blood Advances, 1(7):468-476, 2017), KP457 (Stem Cells Transl Med, 6(3):720-730, 2017), and SR1 (Cell, 174(3):636-648, 2018)

Stem Cell Cure for Kidney Injury: Therapy to Solve Most Complex Issues in Renal System

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Kidney Injury ◽  
Cell Types ◽  
Tissue Remodelling ◽  
Major Health Problem ◽  
In Vivo Experiments ◽  
Renal Regeneration ◽  
Induced Pluripotent

Renal failure is a major health problem. The mortality rate remain high despite of several therapies. The most complex of the renal issues are solved through stem cells. In this review, different mechanism for cure of chronic kidney injury along with cell engraftment incorporated into renal structures will be analysed. Paracrine activities of embryonic or induced Pluripotent stem cells are explored on the basis of stem cell-induced kidney regeneration. Several experiments have been conducted to advance stem cells to ensure the restoration of renal functions. More vigour and organised protocols for delivering stem cells is a possibility for advancement in treatment of renal disease. Also there is a need for pressing therapies to replicate the tissue remodelling and cellular repair processes suitable for renal organs. Stem cells are the undifferentiated cells that have the ability to multiply into several cell types. In vivo experiments on animal’s stem cells have shown significant improvements in the renal regeneration and functions of organs. Nevertheless more studies show several improvements in the kidney repair due to stem cell regeneration.

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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