Functional compensation between hematopoietic stem cell clones in vivo

Abstract

In most organ systems, regeneration is a coordinated effort that involves many stem cells, but little is known about whether and how individual stem cells compensate for the differentiation deficiencies of other stem cells. Functional compensation is critically important during disease progression and treatment. Here, we show how individual hematopoietic stem cell (HSC) clones heterogeneously compensate for the lymphopoietic deficiencies of other HSCs in a mouse. This compensation rescues the overall blood supply and influences blood cell types outside of the deficient lineages in distinct patterns. We find that highly differentiating HSC clones expand their cell numbers at specific differentiation stages to compensate for the deficiencies of other HSCs. Some of these clones continue to expand after transplantation into secondary recipients. In addition, lymphopoietic compensation involves gene expression changes in HSCs that are characterized by increased lymphoid priming, decreased myeloid priming, and HSC self-renewal. Our data illustrate how HSC clones coordinate to maintain the overall blood supply. Exploiting the innate compensation capacity of stem cell networks may improve the prognosis and treatment of many diseases.

Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo

“…3E). Additionally, recent work in our laboratory has shown how HSC differentiation is influenced by the amount of donor HSCs (38) and by the presence of defective HSCs (39). Taken together, these findings suggest that HSC self-renewal and differentiation programs can be altered by transplantation conditions and by environmental conditions and demands.…”

“…Unfortunately, unconditioned transplantation produces low engraftment rates even after repeat transplantations (26,33). In vivo tracking of the few individual HSCs that engraft after unconditioned transplantation was technically prohibitive until the recent development of an in vivo clonal tracking technology (37)(38)(39). This technology uses genetic barcodes drawn from a large semirandom 33-mer DNA barcode library to label and track individual HSCs.…”

Small RNA sequencing reveals a novel tsRNA‐06018 playing an important role during adipogenic differentiation of hMSCs

“…As hMSCs must be grown to confluence over 2 days prior to undergoing adipogenic differentiation, we were unable to assess the adipogenic differentiation of cells overexpressing tsRNA‐06018. Then, the remaining differentially expressed tsRNA did not imply that these tsRNAs were not involved in the process of adipogenic differentiation, possibly due to compensatory biological mechanisms 38‐41 . However, the novel tsRNA‐06018 clearly impacted hMSC adipogenesis.…”

“…Then, the remaining differentially expressed tsRNA did not imply that these tsRNAs were not involved in the process of adipogenic differentiation, possibly due to compensatory biological mechanisms. [38][39][40][41] However, the novel tsRNA-06018 clearly impacted hMSC adipogenesis.…”

Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses

“…In this study, we present an integrated experimental system that directly connects gene expression with cellular behavior at the single cell level by combining synthetic DNA barcode tracking and single cell mRNA sequencing in a PDX model. We have previously demonstrated the high sensitivity and precise quantification of our DNA barcode tracking using hematopoietic stem cells in vivo [36][37][38][39][40] . Here, we adapted the barcode tracking to assay the activities of cancer cells and their gene expression profiles simultaneously in a PDX model xenografted by human B-cell acute lymphoblastic leukemia (B-ALL) samples.…”