Activation of Wnt Signaling in Hematopoietic Regeneration

Abstract

Hematopoietic stem cells (HSCs) respond to injury by rapidly proliferating and regenerating the hematopoietic system. Little is known about the intracellular programs that are activated within HSCs during this regenerative process and how this response may be influenced by alterations in signals from the injured microenvironment. Here we have examined the regenerating microenvironment and find that following injury it has an enhanced ability to support HSCs. During this regenerative phase, both hematopoietic and stromal cell elements within the bone marrow microenvironment show increased expression of Wnt10b, which can function to enhance growth of hematopoietic precursors. In addition, regenerating HSCs show increased activation of Wnt signaling, suggesting that microenvironmental changes in Wnt expression after injury may be integrated with the responses of the hematopoietic progenitors. Cumulatively, our data reveal that growth signals in the hematopoietic system are re-activated during injury, and provide novel insight into the influence of the microenvironment during regeneration.

Wnt3a Reestablishes Osteogenic Capacity to Bone Grafts from Aged Animals

“…T 17,2013 stem-cell populations are Wnt-responsive [66][67][68][69][70] and, using established protocols 51,56 , we confirmed that at least the CD45(-), CD73(1), CD105(1), and Stro1(1) stem-cell and/or stromal-cell population in the bone marrow is Wnt-responsive (Fig. 4).…”

Wnt Signaling in Normal and Malignant Hematopoiesis

“…For example, studies performed on human bone marrow indicate that Wnt-2b, Wnt-5a, and Wnt-10b are expressed in unfractionated bone marrow cells, and that Wnt-5a is expressed in populations enriched for HSCs and progenitors (Van den Berg et al 1998). In the mouse bone marrow, Wnt-5a is expressed by mature B cells (Liang et al 2003), whereas Wnt-10b is produced by myeloid cells, erythrocytes, and immature B cells (Congdon et al 2008). Moreover, the precise expression of Wnt ligand seems to be regulated dynamically during hematopoietic regeneration; whereas Wnt-3a, Wnt-5a, and Wnt-10b are all expressed in the homeostatic murine bone marrow microenvironment (Reya et al 2000), Wnt-10b is specifically up-regulated in the injured murine bone marrow microenvironment (Congdon et al 2008), suggesting that specific Wnts may be particularly adept at or used during regeneration.…”

“…In the mouse bone marrow, Wnt-5a is expressed by mature B cells (Liang et al 2003), whereas Wnt-10b is produced by myeloid cells, erythrocytes, and immature B cells (Congdon et al 2008). Moreover, the precise expression of Wnt ligand seems to be regulated dynamically during hematopoietic regeneration; whereas Wnt-3a, Wnt-5a, and Wnt-10b are all expressed in the homeostatic murine bone marrow microenvironment (Reya et al 2000), Wnt-10b is specifically up-regulated in the injured murine bone marrow microenvironment (Congdon et al 2008), suggesting that specific Wnts may be particularly adept at or used during regeneration. The receptors for these ligands are also extensively expressed (Table 1), with long-term human HSCs expressing Frizzled 6 (Wagner et al 2004).…”

PTH expands short-term murine hemopoietic stem cells through T cells

“…22 Our results are in keeping with those of earlier studies on the role of Wnt signaling in HSPC biology. Studies in models of hemopoietic regeneration have revealed not only that the production of Wnt10b by hemopoietic cells and SCs is strongly upregulated in conditions of hematopoietic recovery, 39 but also that Wnt10b directly induces HSPC expansion. 39 Moreover, It is well established that canonical Wnt signaling regulates HSPC expansion.…”

“…Studies in models of hemopoietic regeneration have revealed not only that the production of Wnt10b by hemopoietic cells and SCs is strongly upregulated in conditions of hematopoietic recovery, 39 but also that Wnt10b directly induces HSPC expansion. 39 Moreover, It is well established that canonical Wnt signaling regulates HSPC expansion. [13][14][15] However, until recently, there has been significant controversy as gain-and loss-of-function studies led to the conclusion that activation of Wnt signaling enhances or depletes the HSPC pool according to the experimental strategy.…”