The Mammoto Lab studies the roles of angiogenesis in organ development, tissue regeneration, aging, disease pathogenesis, and mesenchymal stromal/stem cell (MSC)–based therapies. Our mission is to develop innovative therapeutic concepts and strategies for angiogenesis-related disorders in aging populations. To achieve this goal, we focus on the following translational research projects.
1. The role of angiogenesis in lung regeneration.
Although epithelium is a major player in organ development and regeneration, blood vessels also play crucial roles in these processes. We are trying to understand the mechanism by which endothelial cells control lung development, regeneration and aging using multidisciplinary approaches. To study the mechanism of angiogenesis in the lung, we have developed a unique method to implant hydrogel on the lung surface of a living mouse and successfully recapitulated lung-specific angiogenesis and various cellular interactions in the gel in both physiological and pathological conditions. Our long-term goal is to develop more effective angiogenesis-targeted strategies for lung regeneration.
Vascular niche in lung alveolar development, homeostasis and regeneration.
2. Mechanism of age-dependent decline in angiogenesis.
Aging is associated with impaired angiogenesis, which contributes to the increased susceptibility to age-related lung diseases such as chronic lung diseases. We are investigating molecular mechanism by which aging inhibits lung vascular and alveolar morphogenesis using various transgenic animal models. In addition to soluble growth factors, biophysical factors such as changes in cell size, ECM stiffness, stretching forces, and flow control endothelial cell growth and differentiation. However, the mechanosensitive mechanism of age-dependent decline in angiogenesis and lung alveolar morphogenesis remains unclear. Thus, we also focus on the mechanosensitive mechanism of age-related decline in angiogenesis using various in vitro systems and transgenic animal models.
3. Pulmonary hypertension.
Pulmonary hypertension is a devastating pulmonary vascular disease characterized by aberrant muscularization of the normally non-muscularized distal pulmonary arterioles. We investigate the mechanism by which endothelial signaling controls vascular smooth muscle cell behaviors. We are studying the mechanism by which endothelial signalings control smooth muscle cell behaviors using in vitro assays, a hypoxia-induced experimental PH model, and transgenic animal models.
4. Mesenchymal stem/stromal cell (MSC) pellet implantation therapy.
We have successfully fabricated implantable pellets of human MSCs derived from subcutaneous white adipose tissue without the use of exogenous biomaterials. Surgically implanted MSC pellets under the skin of immunodeficient NSG mice stably engraft and stimulate the formation of local host-derived capillary networks. MSC pellets continuously express a variety of angiogenesis-related factors in vivo and function as a “living drug” within the body. While MSC-pellet implantation has little effects on basic physiological parameters (e.g., body weight, blood pressure, hematocrit) without tumorigenicity, the implantation increases capillary density in specific organs/tissues of the recipient mouse. MSC-pellet implantation also restores post-ischemic capillary rarefaction and prevents tissue hypoxia. The MSC-pellet therapy we have developed can be further optimized by using MSCs derived from alternative tissue sources (e.g., bone marrow, umbilical cord, or placenta) and/or by employing genetically or chemically modified MSCs. Importantly, this platform can be leveraged not only to preclinically assess the in vivo functional fitness of human MSCs, but also to enhance the therapeutic efficacy of MSC-based therapies in humans. This system has the potential to be a game-changing strategy in MSC-based therapy.
Implantation of human mesenchymal stromal cell (MSC)-pellet for therapeutic angiogenesis.
