Hyaluronan Expressed by Bone Marrow Mesenchymal Cells Regulates Functions of the Hematopoietic Microenvironment

• Published in: Blood 2012-11, Vol.120 (21), p.1243-1243
• Main Authors: Goncharova, Valentina, Schraufstaetter, Ingrid U, Iizuka, Shinji, Yamaguchi, Yu, Khaldoyanidi, Sophia K
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.1243.1243

Abstract 1243 While the quantity and quality of transplanted hematopoietic stem cells (HSC) are important for the recovery of hematopoiesis, the functional status of the regulatory hematopoietic microenvironment is a critical parameter that determines the regenerative function of HSCs. The quality of the microenvironment, i.e. its ability to support hematopoiesis, may be compromised under pathological circumstances such as during disease development or as a result of therapeutic interventions. Thus, the hematopoietic microenvironment should be allowed to recover prior to HSC transplantation. To effectively prepare the marrow microenvironment for HSC transplantation it is important to understand which of the molecular pathways regulating the function of the microenvironment are disrupted under the specific pathological condition. The involvement of hyaluronan (HA) in regulation of hematopoiesis has been previously suggested. However, whether HA contributes to the regulatory network of the hematopoietic microenvironment is not well understood. Since HA is highly susceptible to irradiation, which induces HA degradation and depolymerization leading to HA chain fragmentation and affecting its three-dimensional structure, sublethally irradiated mice (6Gy) were used to test the effect of exogenous HA on hematopoietic recovery. We found that administration of HA shortened the period of cytopenia compared to control mice which received vehicle only. To investigate whether the depletion of HA from the microenvironment has negative effects of hematopoietic homeostasis, knockout mice of three hyaluronan synthase genes (Has1, Has2, Has3) were generated as a mouse model of targeted HA deficiency in the hematopoietic microenvironment. Specifically, we generated double Has knockout (KO) mice (dHAS1/3 KO, Has1–/–;Has3–/–) and triple Has KO mice (tHAS1/2/3 KO, Prx1-Cre;Has2flox/flox;Has1–/–;Has3–/–). In the following study, wild type (WT), dHAS1/3 and tHAS1/2/3 KO mice were sublethally irradiated (6Gy) and the dynamics of hematopoietic recovery were tested. We found that the recovery of leukocytes in tHAS1/2/3 KO mice was significantly delayed as compared to WT and dHAS1/3 KO mice. This finding suggests that the HA-deficient microenvironment cannot support hematopoietic recovery following irradiation. Additional tests demonstrated that the number of hematopoietic progenitors was decreased in bone marrow and increased in extramedullary sites of tHAS1/2/3 KO mice as compared