Justin Chong, Biological Sciences, Summer 2021
Figure: A hematopoietic stem cell can give rise to all hematopoietic lineages, such as myeloid, lymphoid and erythroid outputs.
Image Source: Wikimedia Commons, OpenStax Anatomy and Physiology
The transition of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) from the fetal stage to the adult stage shapes fetal, neonatal, and adult hematopoiesis, or production of all blood components. It is important to examine as it has implications for a wide variety of blood disorders. HSCs are immature cells that can develop into all types of blood cells, and HPCs are HSCs that have committed and are restricted to a certain blood cell type fate (Bryder et al. 2006). A study by Li and Magee from the Washington University School of Medicine discovered that the transition of transcriptional and epigenetic profiles of HSCs and HPCs from the fetal to adult stage is loosely timed and uncoordinated (Li & Magee 2021). They found that this transition is associated with the initiation of type 1 interferon signaling that turns on adult-related genes but makes HSCs and HPCs vulnerable to mutations that promote leukemogenesis in children. These unique driver mutation profiles caused by the pulse of type 1 interferon signaling may be the reason why pediatric leukemia, genotypically and phenotypically, is very distinct from adult leukemia.
Fetal and adult HSCs are drastically different. Fetal HSCs divide without losing their self-renewal capacity, which is the ability of daughter cells to proliferate at the same level of the parent cell. On the other hand, adult HSCs deplete their self-renewal capacity after several divisions, so they are eventually destined to become terminally differentiated (Al-Hajj & Clarke 2004). In terms of their lineage biases, fetal HSCs generate lymphoid (immune) and myeloid (bone marrow origin) outputs at similar efficiencies, while adult HSCs primarily differentiate into the myeloid fate. Fetal and adult HSCs also have differing transcriptomes, which is the set of all coding and non-coding mRNA transcripts produced by a population of cells (Hoejimakers et al. 2012).
Mouse HSCs were long thought to experience an abrupt transition from the fetal to adult state three to four weeks after birth. However, through single-cell RNA-sequencing and epigenome profiling assays, Li and Magee found that this transition is gradual rather than sudden. This transition is marked by upregulation of adult identity HSC genes and downregulation of fetal identity HSC genes occurs. They also discovered that these changes begin during late gestation, contrary to the belief that this transition began postnatally. In addition, they also found that HSCs do not all begin their transition together; there is no consistent regulatory network or stimuli that guides and coordinates the transition in a population of cells simultaneously. Instead, these cells act independently in their transition, but the population will arrive at the adult state synchronously.
Unlike differentiating embryonic and somatic stem cells that use epigenetic alterations and enhancers to upregulate the expression of genes that specify a certain cell lineage and repress other cell fates, HSCs are imprecisely timed and uncoordinated in their transition and lack robust gene regulation (Brand et al. 2019). The authors suggest that transcription at individual loci is stochastic, or randomly determined, and that weak enhancer elements, which are responsible for enhancing transcription of genes by acting on their respective promoters, are responsible for the uncoordinated nature of the HSC fetal-to-adult transition. Once these suboptimized enhancer elements bind a transcriptional factor and initiate the transition, they become stronger and more stable by recruiting cofactors and modifying nearby chromatin. This causes transcriptional bursts of adult-identity HSC genes to become more frequent and larger, ensuring that the transition from the fetal to the adult state moves forward (Li et al. 2020). The weakness of these enhancers is determined by the order, orientation, and spacing of binding sites within the enhancer (Farley et al. 2016).
The authors also posit that a pulse of type I interferon signaling is a potential chronic stimulus that activates and maintains this transition. These cytokines initiate adult gene expression in HSCs and HPCs and cause the proliferation of the HSC population before birth (Jassinskaja et al. 2017). This burst of type I interferon production occurs in the fetal skin independent of infection, indicating that some unknown transition in the developing skin drives type 1 interferon expression and consequently adult gene expression programs.
The heterogeneous nature of the transcriptional and epigenetic landscapes among HSC and HPC populations explains why only some cells are vulnerable to leukemogenic mutations, which have different effects on HSCs and HPCs depending on cell stage (fetal, neonatal, or adult). This opens up a new avenue for research into treating leukemia, as researchers can begin to identify and isolate genetic programs that make cells more susceptible to leukemogenic mutations, and then reprogram cells to more leukemia-resistant gene expression profiles (Li et al. 2020). However, many questions remain unanswered, especially regarding how this knowledge applies to humans, who experience gestational hematopoietic development much earlier than mice and over a more prolonged period of time.
References
Al-Hajj, M. & Clarke, M. F. (2004). Self-renewal and solid tumor stem cells. Oncogene 23: 7274-7282. https://doi.org/10.1038/sj.onc.1207947.
Brand, M. et al. (2019). Polycomb/trithorax antagonism: cellular memory in stem cell fate and function. Cell Stem Cell 24(4): 518-533. https://doi.org/10.1016/j.stem.2019.03.005.
Bryder, D. et al. (2006). Hematopoietic stem cells. The American Journal of Pathology 169(2): 338-346. https://doi.org/10.2353/ajpath.2006.060312.
Farley, E. K. et al. (2016). Syntax compensates for poor binding sites to encode tissue specificity of developmental enhancers. PNAS 113(23): 6508-6513. https://doi.org/10.1073/pnas.1605085113.
Hoejimakers, W. A. M. et al. (2012). Transcriptome analysis using RNA-seq. Methods in Molecular Biology 923: 221-239. https://doi.org/10.1007/978-1-62703-026-7_15.
Jassinskaja, M. et al. (2017). Comprehensive proteomic characterization of ontogenic changes in hematopoietic stem and progenitor cells. Cell Reports 21(11): 3285-3297. https://doi.org/10.1016/j.celrep.2017.11.070.
Li, Y. et al. (2020). Single-cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins before birth. Cell Stem Cell 27(5): 732-747. https://doi.org/10.1016/j.stem.2020.08.001.
Li, Y. & Magee, J. A. (2021). Transcriptional reprogramming in neonatal hematopoietic stem and progenitor cells. Experimental Hematology. https://doi.org/10.1016/j.exphem.2021.07.004.