REGULATION OF STRESS ERYTHROPOIESIS: INTERACTION BETWEEN MICROENVIRONMENT AND STRESS ERYTHROID PROGENITORS
Open Access
- Author:
- Xiang, Jie
- Graduate Program:
- Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 19, 2014
- Committee Members:
- Robert Paulson, Dissertation Advisor/Co-Advisor
Robert Paulson, Committee Chair/Co-Chair
Ross Cameron Hardison, Committee Member
Zhi Chun Lai, Committee Member
Kumble Sandeep Prabhu, Committee Member
Yanming Wang, Committee Member
Naomi S Altman, Committee Member - Keywords:
- Stress erythropoiesis
Stem cell
Epo
progenitors
Anemia - Abstract:
- Steady-state erythropoiesis occurs in the bone marrow and produces erythrocytes at a constant rate. Its role is to replace “worn out” red blood cells that are removed by the spleen. While in response to acute anemia and tissue hypoxia, another type of erythropoiesis, stress erythropoiesis, is induced to rapidly generate new erythrocytes to compensate the loss. Previously our lab showed that stress erythropoiesis utilizes various signals and stress erythroid progenitors that are distinct from steady state erythropoiesis. Initially, bone marrow CD34+KSL cells migrate into the spleen and interact with hedgehog ligands, which induce the expression of BMP4. Hedgehog and BMP4 together specify the stress erythroid fate. Further work showed that there are three distinct populations of stress erythroid progenitors that expand in the spleen during the recovery from bone marrow transplantation. They were identified as Population I (Kit+CD71-/medTer119lo/-), Population II (Kit+CD71highTer119med) and Population III (Kit+CD71-/medTer119high). The appearance of three populations suggested the temporal order for their development: Population I gives rise to Population II and Population II gives rise to Population III. Although the number of Population I cells increased in the pre-recovery stage, we didn’t observe stress BFU-E until day 8, which indicated that these cells proliferated but couldn’t differentiate in the early time. Then they acquired the ability to differentiate into stress BFU-E. Finally, BMP4, SCF and hypoxia are required for the expansion and differentiation of stress BFU-E during the late stage of the recovery from acute anemia. My work mainly focuses on the following questions: 1. What is the role of GDF15 in the regulation of stress erythropoiesis? 2. How to identify the self-renewing Population I cells and differentiating Population I cells? 3. How does Epo regulate the transition from expansion to differentiation of stress erythroid progenitors? These questions will be answered in Chapters 2, 3 and 4. In Chapter 2, my work showed that GDF15-/- mice are deficient in recovery from acute anemia and fail to provide short-term radioprotection. GDF15 plays a critical role in stress erythropoiesis by inducing and maintain hypoxia dependent BMP4 expression. My work in chapter 3 further described the development of distinct stress erythroid progenitors with increasing maturity based on their expression of cell surface markers CD34, CD133, Kit and Sca1. Here we developed an in vitro culture system and identified CD34+CD133+KS population as the early stress erythroid progenitors that have self-renewal ability and CD34-CD133-KS population as the later stress erythroid progenitors that have differentiation ability. The bone marrow transplantation data also showed CD34+CD133+KS cells expanded on day6 and CD34-CD133-KS cells were increased on day 12 post-transplantation. Then I further demonstrated that similar to murine bone marrow, human bone marrow contains cells can exhibit stress erythropoiesis ability and generate BMP4 dependent stress BFU-E. Finally my work in Chapter 4 showed that hypoxia and Epo induce the transition from expansion to differentiation of stress erythroid progenitors. The interaction between microenvironment and stress erythroid progenitors contributes a key part in regulating stress erythropoiesis. Wnt signaling produced by macrophages involves in the expansion of early stress erythroid progenitors. Epo stimulates macrophages through Stat5 signaling pathway to down regulate Wnt signaling and increase Prostaglandin E2 production to induce the differentiation of stress erythroid progenitors. The characterization of stress erythroid progenitors and the signals that regulate their development potentially provide new therapeutics to treat anemia and improve the recovery from bone marrow transplants.