CXCL12/CXCR4 Signaling Enhances Human PSC-Derived Hematopoietic Progenitor Function and Overcomes Early In Vivo Transplantation Failure
| Autor: | Mickie Bhatia, Allison L. Boyd, Jennifer C. Reid, Tony J. Collins, Deanna P. Porras, Borko Tanasijevic, Diana Golubeva |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pluripotent Stem Cells Receptors CXCR4 bone marrow human pluripotent medicine.medical_treatment Bone Marrow Cells Hematopoietic stem cell transplantation Biology Biochemistry CXCR4 Article 03 medical and health sciences Mice Genetics medicine cell signaling Animals Humans Progenitor cell Induced pluripotent stem cell lcsh:QH301-705.5 progenitors lcsh:R5-920 Hematopoietic Stem Cell Transplantation chemokine receptor Cell Biology Hematopoietic Stem Cells Chemokine CXCL12 Cell biology Transplantation Haematopoiesis Kinetics 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) embryonic structures Bone marrow Stem cell lcsh:Medicine (General) Developmental Biology transplantation Signal Transduction |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 10, Iss 5, Pp 1625-1641 (2018) |
| ISSN: | 2213-6711 |
| Popis: | Summary Human pluripotent stem cells (hPSCs) generate hematopoietic progenitor cells (HPCs) but fail to engraft xenograft models used to detect adult/somatic hematopoietic stem cells (HSCs) from donors. Recent progress to derive hPSC-derived HSCs has relied on cell-autonomous forced expression of transcription factors; however, the relationship of bone marrow to transplanted cells remains unknown. Here, we quantified a failure of hPSC-HPCs to survive even 24 hr post transplantation. Across several hPSC-HPC differentiation methodologies, we identified the lack of CXCR4 expression and function. Ectopic CXCR4 conferred CXCL12 ligand-dependent signaling of hPSC-HPCs in biochemical assays and increased migration/chemotaxis, hematopoietic progenitor capacity, and survival and proliferation following in vivo transplantation. This was accompanied by a transcriptional shift of hPSC-HPCs toward somatic/adult sources, but this approach failed to produce long-term HSC xenograft reconstitution. Our results reveal that networks involving CXCR4 should be targeted to generate putative HSCs with in vivo function from hPSCs. Graphical Abstract Highlights • Transplant kinetics indicate human PSC-HPCs fail in the first 24 hr in bone marrow • hPSC-HPCs aberrantly express chemokine receptors, specifically lacking CXCR4 • Ectopic CXCR4 enhances hPSC-HPC function in vitro and transplantation in vivo • CXCR4 linked with global transcriptional shift of hPSC-HPCs toward somatic HPCs Bhatia and colleagues reveal that human PSC-derived hematopoietic progenitor cells fail to survive even 24 hr following in vivo bone marrow transplantation, while these same progenitors survive and proliferate for weeks in vitro. They link these observations to deficiencies in CXCR4 signaling, which, when rectified, lead to enhanced progenitor function and survival in the bone marrow and a transcriptional shift toward somatic hematopoietic stem cells gene profiles. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|