Biology subjects

Garcia-Alaman, A.

Publications and source records attributed to Garcia-Alaman, A..

3 recordsLinked to original sources

bioRxiv2026

Sodium tungstate promotes vascularization to support beta bell replacement in diabetes

Insufficient vascularization remains a major obstacle to the success of cell-based therapies for diabetes. Building on prior findings that loss of the phosphatase PTP1B enhances VEGFA production and improves graft vascularization, we investigated sodium tungstate (NaW), a pharmacological phosphatase inhibitor, as a strategy to improve transplantation outcomes. Using human fibroblast-derived insulin-producing cells and human stem cell-derived islets transplanted into the anterior chamber of the eye in immunodeficient mice, we show that NaW treatment significantly increases both vascularized area and insulin-positive tissue area, while reducing apoptosis within transplanted cells. Mechanistically, NaW upregulates VEGFA expression in transplanted cells and amplifies VEGFA-induced endothelial cell proliferation, migration, and tubulogenesis via MAPK/ERK signalling. These dual effects, which encompass stimulating both endocrine and endothelial compartments, lead to enhanced integration and function of transplanted cells. Importantly, the pro-angiogenic effects of NaW occur independently of exogenous endothelial cell supplementation, relying solely on the hosts endogenous endothelial cells. These findings position NaW, and potentially other phosphatase inhibitors, as promising adjuncts to improve vascularization, survival, and therapeutic efficacy in clinical cell-based transplantation protocols for diabetes. One-sentence summaryProangiogenic role of sodium tungstate in transplantation

physiology↗

bioRxiv2026

Uncovering the function of Wisp1 in whole-body glucose homeostasis: insights from Wisp1 knockout mice

WNT1-inducible signaling pathway protein 1 (Wisp1/CCN4) is a matricellular protein implicated in inflammation and metabolic dysfunction in obesity, yet its role in whole-body glucose metabolism remains unclear. In this study, Wisp1 knockout (KO) mice were analysed under physiological and high-fat (HF) diet conditions to define its impact on metabolic regulation. Neither physiological nor HF diet conditions revealed an effect of Wisp1 deficiency on whole-body glucose tolerance. However, male KO mice on a HF diet exhibited enhanced insulin sensitivity, lower insulin levels, and a marked reduction in adipose tissue inflammation, as evidenced by diminished macrophage infiltration and decreased pro-inflammatory cytokine expression in visceral fat. Additionally, beta cell mass expansion was attenuated in KO mice under HF diet, aligning with lower macrophage infiltration in islets. These findings suggest that improved insulin sensitivity in KO mice occurs independently of changes in glucose tolerance, likely due to mitigated adipose tissue inflammation. Thus, Wisp1 primarily modulates local adipose inflammatory responses, indirectly affecting islet adaptation to metabolic stress, rather than serving as a direct regulator of systemic glucose homeostasis.

physiology↗

bioRxiv2021

Direct reprogramming of human fibroblasts into insulin-producing cells by transcription factors

Direct lineage reprogramming of one somatic cell into another bypassing an intermediate pluripotent state has emerged as an alternative to embryonic or induced pluripotent stem cell differentiation to generate clinically relevant cell types. One cell type of clinical interest is the pancreatic {beta} cell that secretes insulin and whose loss and/or dysfunction leads to diabetes. Generation of functional {beta}-like cells from developmentally related somatic cell types (pancreas, liver, gut) has been achieved via enforced expression of defined sets of transcription factors. However, clinical applicability of these findings is challenging because the starting cell types are not easily obtainable. Skin fibroblasts are accessible and easily manipulated cells that could be a better option, but available studies indicate that their competence to give rise to {beta} cells through similar direct reprogramming approaches is limited. Here, using human skin fibroblasts and a protocol that ensures high and consistent expression of adenovirus-encoded reprogramming factors, we show that the transcription factor cocktail consisting of Pdx1, Ngn3, MafA, Pax4 and Nkx2-2 activates key {beta} cell genes and down-regulates the fibroblast transcriptional program. The converted cells produce insulin and exhibit intracellular calcium responses to glucose and/or membrane depolarization. Furthermore, they secrete insulin in response to glucose in vitro and after transplantation in vivo. These findings demonstrate that transcription factor-mediated direct reprogramming of human fibroblasts is a feasible strategy to generate insulin-producing cells.

developmental biology↗