Developmental differences between neonatal and adult human erythropoiesis

Yan, Hongxia; Hale, John; Jaffray, Julie; Li, Jie; Wang, Yaomei; Huang, Yu‐Min; An, Xiuli; Hillyer, Christopher D.; Wang, Nan; Kinet, Sandrina; Taylor, Naomi; Mohandas, Narla; Narla, Anupama; Blanc, Lionel

doi:10.1002/ajh.25015

Cited by 53 publications

(59 citation statements)

References 41 publications

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“…The finding that Dex markedly enhanced the erythroid proliferation of CD34 + cells from adult PB but not the proliferation of CD34 + cells derived from CB was unexpected and very surprising. In conjunction with our previous finding of different trajectories in the transition from BFU-E to CFU-E between CD34 + cells from adult PB and CB this finding implies that Dex has differential effects on transitional erythroid progenitor populations that is dependent on the developmental state (29). The use of enriched populations of human BFU-E and CFU-E cells enabled us to define that the CFU-E derived from adult human PB and not BFU-E are responsive to Dex.…”

Section: Discussionsupporting

confidence: 83%

“…We previously described that based on surface expression of CD34 and CD36 we can obtain highly enriched population of BFU-E (GPA -IL3R -CD34 + CD36 -) and CFU-E (GPA -IL3R -CD34 -CD36 + ) (18). More recently we reported a transitional progenitor population defined as GPA -IL3R -CD34 + CD36 + which is more predominant during differentiation of adult PB than that of CB (29). Notably, the kinetics of progression through these differentiation states were also altered with Dex treatment (Figure 2A).…”

Section: Dex Targets a Subpopulation Of Adult Cfu-esmentioning

confidence: 99%

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Glucocorticoids Induce the Expansion of an Immature Human CFU-E Population

Ashley

Yan

Wang

et al. 2019

Preprint

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Despite effective clinical use, the mechanistic bases for the regulation of human erythropoiesis by glucocorticoids remain poorly understood. Here, we employed an erythroid culture system to differentiate primary human CD34 + cells isolated from control peripheral blood, cord blood and patients with Diamond Blackfan anemia (DBA), as model of an erythropoietic disorder treated with glucocorticoids. We found that the response to Dexamethasone is dependent on the developmental origin of the source of CD34 + cells, specifically increasing the expansion of CD34 + cells from peripheral blood but not cord blood. We also demonstrated that Dex treatment leads to the expansion of a novel immature colony-forming unit-erythroid (CFU-E) population in peripheral blood which is uniquely responsible for the proliferative effects observed during human adult erythropoiesis. Dex treatment of peripheral blood CFU-E cells also induced p57 Kip2 expression while patients with DBA resistant to steroids had altered p57 Kip2 expression that did not increase with Dex. Furthermore, shRNA knockdown of p57 Kip2 reduced proliferation and abrogated the effects of Dex. Finally, proteomics of Dex-treated CFU-E from peripheral blood and cord blood additionally revealed novel Dex targets in the erythroid system.Altogether, these results provide novel insights into the regulation of human erythropoiesis by glucocorticoids.3 Introduction:

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Section: Discussionsupporting

confidence: 83%

Section: Dex Targets a Subpopulation Of Adult Cfu-esmentioning

confidence: 99%

Glucocorticoids Induce the Expansion of an Immature Human CFU-E Population

Ashley

Yan

Wang

et al. 2019

Preprint

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“…Having established genetic confidence in our hit set, we next investigated whether the selected genes satisfied enrichment criterion within the erythroid branch of hematopoiesis. RNA expression values for each of the 77 hit genes were examined in datasets spanning human hematopoiesis (Corces et al, 2016), as well as adult and fetal erythropoiesis (Yan et al, 2018) ( Figure 3E,F; Figure S3G). In the more holistic hematopoiesis dataset, common myeloid progenitors (CMPs) and megakaryocyte-erythroid progenitors (MEPs) were significantly enriched for hit genes (p < 0.01).…”

Section: Screenmentioning

confidence: 99%

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

Nandakumar

McFarland

Mateyka

et al. 2018

Preprint

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Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in noncoding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes.Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits.We applied a gene-centric loss-of-function screening approach to GWAS of RBC traits. We focused on 75 loci associated with RBC traits that were identified by a GWAS performed in up to 135,000 individuals (van der Harst et al., 2012) spanning 6 RBC traits ( Figure S1A). Importantly, these 75 loci have been robustly replicated and show large effect sizes in more recently reported association studies performed on larger cohorts and thus represent ideal targets for perturbation studies (Astle et al., 2016;Lareau et al., 2018). We endeavored to select all genes that could potentially underlie these 75 GWAS signals. To do this, each of the 75 sentinel SNPs was first expanded to a linkage disequilibrium (LD) block including all SNPs in high LD (r 2 > 0.8, Figure 1A, Figure S1B), then further to the nearest genomic recombination hotspot. Based upon insights from previous expression quantitative trait locus (eQTL) studies (Montgomery and Dermitzakis, 2011; Rossin et al., 2011;Veyrieras et al., 2008), each gene annotated in the genome was expanded to include a wingspan encompassing 110 kb upstream and 40 kb downstream of the transcriptional start and end sites, respectively, to also capture potential functional regulatory elements. This resulted in selection of 389 genes overlapping or in the vicinity of the LD blocks to be tested in the pooled loss-of-function screen. These were distributed at a median of 4 genes per loci ( Figure S1C).Since the majority of common genetic variation underlying RBC traits appears to act in a cellintrinsic manner within the erythroid lineage, we decided to perturb the candidate genes during the process of human erythropoiesis Sankaran et al., 2012;Sankaran et al., 2008;Ulirsch et al., 2016). We chose a pooled short hairpin RNA (shRNA) based loss-of-

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“…In light of the practical limitations associated with SCs, there has been growing enthusiasm for the use of both precursor and stem cell–based therapies (we use the term “stem cell” throughout this review to maintain consistency while recognizing that few of the cell sources mentioned are true stem cells) for peripheral nerve regeneration . We are also cognizant of the fact that embryonic stem cells generally have a higher regenerative capacity and are less lineage committed than adult precursor and/or stem cells . There is a growing body of evidence in preclinical animal studies showing that stem cells play a positive role in the regeneration of peripheral nerves after injury .…”

Section: Introductionmentioning

confidence: 99%

“…[26][27][28][29] We are also cognizant of the fact that embryonic stem cells generally have a higher regenerative capacity and are less lineage committed than adult precursor and/or stem cells. 30,31 There is a growing body of evidence in preclinical animal studies showing that stem cells play a positive role in the regeneration of peripheral nerves after injury. [32][33][34][35][36][37] These effects are thought to be based on the ability of transplanted stem cells to promote regeneration by cell differentiation into tissuespecific cell types, [38][39][40] signaling through cell-to-cell contact, and/or sustained release of neurotrophic factors.…”

mentioning

confidence: 99%

Stem‐cell–based therapies to enhance peripheral nerve regeneration

et al. 2019

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Peripheral nerve injury remains a major cause of morbidity in trauma patients. Despite advances in microsurgical techniques and improved understanding of nerve regeneration, obtaining satisfactory outcomes after peripheral nerve injury remains a difficult clinical problem. There is a growing body of evidence in preclinical animal studies demonstrating the supportive role of stem cells in peripheral nerve regeneration after injury. The characteristics of both mesoderm‐derived and ectoderm‐derived stem cell types and their role in peripheral nerve regeneration are discussed, specifically focusing on the presentation of both foundational laboratory studies and translational applications. The current state of clinical translation is presented, with an emphasis on both ethical considerations of using stems cells in humans and current governmental regulatory policies. Current advancements in cell‐based therapies represent a promising future with regard to supporting nerve regeneration and achieving significant functional recovery after debilitating nerve injuries.

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Developmental differences between neonatal and adult human erythropoiesis

Cited by 53 publications

References 41 publications

Glucocorticoids Induce the Expansion of an Immature Human CFU-E Population

Glucocorticoids Induce the Expansion of an Immature Human CFU-E Population

Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

Stem‐cell–based therapies to enhance peripheral nerve regeneration

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