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Conditioning for hematopoietic transplantation activates the complement cascade and induces a proteolytic environment in bone marrow: a novel role for bioactive lipids and soluble C5b-C9 as homing factors.

Kim CH, Wu W, Wysoczynski M, Abdel-Latif A, Sunkara M, Morris A, Kucia M, Ratajczak J, Ratajczak MZ - Leukemia (2011)

Bottom Line: As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC).Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs.We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.

ABSTRACT
We have observed that conditioning for hematopoietic transplantation by lethal irradiation induces a proteolytic microenvironment in the bone marrow (BM) that activates the complement cascade (CC). As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC). At the same time, proteolytic enzymes induced in irradiated BM impair the chemotactic activity of α-chemokine stromal-derived factor-1 (SDF-1). As SDF-1 is considered a crucial BM chemoattractant for transplanted hematopoietic stem/progenitor cells (HSPCs), we sought to determine whether other factors that are resistant to proteolytic enzymes have a role in this process, focusing on proteolysis-resistant bioactive lipids. We found that the concentrations of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) increase in the BM after conditioning for transplantation and that both S1P and, as we show here for the first time, C1P are potent chemoattractants for HSPCs. Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs. In support of a role for MAC in homing and engraftment, we found that soluble MAC enhances in a CR3 (CD11b/CD18)-dependent manner the adhesion of HSPCs to BM stromal cells and increases the secretion of SDF-1 by BM stroma. We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

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The involvement of bioactive lipids in homing and engraftment of HSPCsConditioning for transplantation by radio-chemotherapy induces a proteolytic microenvironment in BM and activates the complement cascade, which leads to generation of soluble MAC. Several proteolytic enzymes are released that decrease the SDF-1 level in BM. At the same time, BM cells damaged by conditioning for transplantation by lethal irradiation release C1P and S1P, which are bioactive lipids resistant to proteolytic enzymes. As potent chemoattractants, both play an important role in homing of stem cells to BM. In addition, MAC generated by CC activation enhances adhesiveness of HSPCs to BM stroma and secretion of SDF-1 by these cells. This increase in SDF-1 secretion may somehow ameliorate the drop in SDF-1 level in such a highly proteolytic microenvironment. What is not shown in this scheme is that CC cleavage fragments, such as C3a and iC3b, also contribute to the homing of HSPCs, as reported by us in the past 3, 14. By increasing the PGE2 level in BM, these CC cleavage fragments level may also modulate the seeding of HSPCs in BM, in addition to the bioactive lipids C1P and S1P.
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Figure 7: The involvement of bioactive lipids in homing and engraftment of HSPCsConditioning for transplantation by radio-chemotherapy induces a proteolytic microenvironment in BM and activates the complement cascade, which leads to generation of soluble MAC. Several proteolytic enzymes are released that decrease the SDF-1 level in BM. At the same time, BM cells damaged by conditioning for transplantation by lethal irradiation release C1P and S1P, which are bioactive lipids resistant to proteolytic enzymes. As potent chemoattractants, both play an important role in homing of stem cells to BM. In addition, MAC generated by CC activation enhances adhesiveness of HSPCs to BM stroma and secretion of SDF-1 by these cells. This increase in SDF-1 secretion may somehow ameliorate the drop in SDF-1 level in such a highly proteolytic microenvironment. What is not shown in this scheme is that CC cleavage fragments, such as C3a and iC3b, also contribute to the homing of HSPCs, as reported by us in the past 3, 14. By increasing the PGE2 level in BM, these CC cleavage fragments level may also modulate the seeding of HSPCs in BM, in addition to the bioactive lipids C1P and S1P.

Mentions: Based on these findings, we propose a new paradigm in which S1P and C1P play an important role in homing of HSPCs. While S1P is a major chemoattractant that directs egress of HSPCs from BM into PB, C1P is released from damaged cells in BM after myeloablative conditioning and, together with SDF-1 and S1P, creates a homing gradient for circulating HSPCs (Figure 7). In addition, the pro-homing effects of both bioactive lipids are positively modulated by the end product of CC activation, which is sMAC. We also propose that S1P, C1P, and sMAC play a more universal role in trafficking of stem cells than previously thought and are involved in regulating the migration of circulating mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like (VSEL) stem cells 25, 30, 42, 43. Accordingly, while S1P plays a role in egress of these cells into PB, C1P, together with S1P locally released from damaged cells (e.g., in infarcted myocardium or brain tissue after stroke) and SDF-1 may chemoattract circulating stem cells for organ repair.


Conditioning for hematopoietic transplantation activates the complement cascade and induces a proteolytic environment in bone marrow: a novel role for bioactive lipids and soluble C5b-C9 as homing factors.

Kim CH, Wu W, Wysoczynski M, Abdel-Latif A, Sunkara M, Morris A, Kucia M, Ratajczak J, Ratajczak MZ - Leukemia (2011)

The involvement of bioactive lipids in homing and engraftment of HSPCsConditioning for transplantation by radio-chemotherapy induces a proteolytic microenvironment in BM and activates the complement cascade, which leads to generation of soluble MAC. Several proteolytic enzymes are released that decrease the SDF-1 level in BM. At the same time, BM cells damaged by conditioning for transplantation by lethal irradiation release C1P and S1P, which are bioactive lipids resistant to proteolytic enzymes. As potent chemoattractants, both play an important role in homing of stem cells to BM. In addition, MAC generated by CC activation enhances adhesiveness of HSPCs to BM stroma and secretion of SDF-1 by these cells. This increase in SDF-1 secretion may somehow ameliorate the drop in SDF-1 level in such a highly proteolytic microenvironment. What is not shown in this scheme is that CC cleavage fragments, such as C3a and iC3b, also contribute to the homing of HSPCs, as reported by us in the past 3, 14. By increasing the PGE2 level in BM, these CC cleavage fragments level may also modulate the seeding of HSPCs in BM, in addition to the bioactive lipids C1P and S1P.
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Related In: Results  -  Collection

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Figure 7: The involvement of bioactive lipids in homing and engraftment of HSPCsConditioning for transplantation by radio-chemotherapy induces a proteolytic microenvironment in BM and activates the complement cascade, which leads to generation of soluble MAC. Several proteolytic enzymes are released that decrease the SDF-1 level in BM. At the same time, BM cells damaged by conditioning for transplantation by lethal irradiation release C1P and S1P, which are bioactive lipids resistant to proteolytic enzymes. As potent chemoattractants, both play an important role in homing of stem cells to BM. In addition, MAC generated by CC activation enhances adhesiveness of HSPCs to BM stroma and secretion of SDF-1 by these cells. This increase in SDF-1 secretion may somehow ameliorate the drop in SDF-1 level in such a highly proteolytic microenvironment. What is not shown in this scheme is that CC cleavage fragments, such as C3a and iC3b, also contribute to the homing of HSPCs, as reported by us in the past 3, 14. By increasing the PGE2 level in BM, these CC cleavage fragments level may also modulate the seeding of HSPCs in BM, in addition to the bioactive lipids C1P and S1P.
Mentions: Based on these findings, we propose a new paradigm in which S1P and C1P play an important role in homing of HSPCs. While S1P is a major chemoattractant that directs egress of HSPCs from BM into PB, C1P is released from damaged cells in BM after myeloablative conditioning and, together with SDF-1 and S1P, creates a homing gradient for circulating HSPCs (Figure 7). In addition, the pro-homing effects of both bioactive lipids are positively modulated by the end product of CC activation, which is sMAC. We also propose that S1P, C1P, and sMAC play a more universal role in trafficking of stem cells than previously thought and are involved in regulating the migration of circulating mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs), and very small embryonic-like (VSEL) stem cells 25, 30, 42, 43. Accordingly, while S1P plays a role in egress of these cells into PB, C1P, together with S1P locally released from damaged cells (e.g., in infarcted myocardium or brain tissue after stroke) and SDF-1 may chemoattract circulating stem cells for organ repair.

Bottom Line: As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC).Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs.We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.

ABSTRACT
We have observed that conditioning for hematopoietic transplantation by lethal irradiation induces a proteolytic microenvironment in the bone marrow (BM) that activates the complement cascade (CC). As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC). At the same time, proteolytic enzymes induced in irradiated BM impair the chemotactic activity of α-chemokine stromal-derived factor-1 (SDF-1). As SDF-1 is considered a crucial BM chemoattractant for transplanted hematopoietic stem/progenitor cells (HSPCs), we sought to determine whether other factors that are resistant to proteolytic enzymes have a role in this process, focusing on proteolysis-resistant bioactive lipids. We found that the concentrations of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) increase in the BM after conditioning for transplantation and that both S1P and, as we show here for the first time, C1P are potent chemoattractants for HSPCs. Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs. In support of a role for MAC in homing and engraftment, we found that soluble MAC enhances in a CR3 (CD11b/CD18)-dependent manner the adhesion of HSPCs to BM stromal cells and increases the secretion of SDF-1 by BM stroma. We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

Show MeSH
Related in: MedlinePlus