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Comparing therapeutic potency of healthy and disease-derived human mesenchymal stromal cells in experimental diabetic nephropathy
Diabetic kidney disease (DKD) is the most common cause of kidney failure in the United States and has no adequate cure. Regenerative medicine, applying cell-based therapy is a promising treatment option for DKD. Mesenchymal stromal/stem cells (MSC) possess paracrine anti-fibrotic, anti-apoptotic, pro-angiogenic, anti-inflammatory, and immunomodulatory regenerative activities that aid in kidney repair in animal models of early DKD. MSC may be harvested from the tissue of patients (autologous) or healthy donors (allogeneic) and administered to treat DKD. However, it is unclear whether autologous MSC, favored for decreased risk of allosensitization and reduced immune cell destruction, is equally effective as allogeneic MSC in rejuvenating the repair process of diabetic kidneys. Furthermore, most studies to date test repair capacity in animals with kidney lesions mimicking early human DKD. However, cell-based therapy is likely to also benefit those with advanced DKD. Thus, studies in animal models of advanced DKD are needed to optimize treatment strategies and enable translation from the bench to the bedside. Finally, there is also a need for non-invasive testing of kidney injury and repair biomarkers, such as relevant profibrotic or inflammatory factors and kidney tissue hypoxia that may contribute to our understanding of processes that promote DKD. Our long-term goal is to develop a novel cell-based therapy for DKD. Interim findings from our Phase I, autologous MSC trial in renovascular disease show safety and evidence of preserved kidney function and reduced kidney hypoxia after 3 months compared to medically-treated controls. Based on these exciting findings, we recently launched a pilot trial applying autologous MSC in individuals with DKD. In preparation for this trial, we tested human DKD-MSC function finding some impairment but preserved paracrine repair activities. Still, it remains unclear how these changes reflect MSC reparative capacity when administered to animals or humans. Thus, there is a critical need to determine the impact of cell source on MSC reparative capacity in the damaged kidney, to tailor and leverage cell based treatments for DKD. Our hypothesis underlying the proposed studies is that MSC harvested from individuals with DKD have comparable kidney repair effects in vivo to age-matched controls. Hence the proposed DiaComp Pilot and Feasibility studies aim to compare kidney repair capacity of DKD-MSC and age-matched Control-MSC with two approaches: 1) Transplantation of human adipose-derived MSC in two obese, Type 2 diabetes mouse models (eNOS-/- db/db and db AngII) and 2) Assessment of mouse kidney repair effects in vivo by measuring changes in albuminuria, kidney function, inflammation, fibrosis, microvascular density and a non-invasive biomarker of kidney hypoxia. Significance: Cell-based therapy to delay DKD progression is extremely promising. Assessing the most optimal cell source (autologous or allogeneic) and/or need for autologous cell preconditioning treatments could lead to successful large-scale clinical trials testing the therapeutic potential of MSC in DKD and other chronic diseases.
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Comparing therapeutic potency of healthy and disease-derived human mesenchymal stromal cells in experimental diabetic nephropathy (Hickson, LaTonya)
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Year: 2021; Items: 2
Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis.
Isik B, Thaler R, Goksu BB, Conley SM, Al-Khafaji H, Mohan A, Afarideh M, Abumoawad AM, Zhu XY, Krier JD, Saadiq IM, Tang H, Eirin A, Hickson LJ, van Wijnen AJ, Textor SC, Lerman LO, Herrmann SM
Stem cell research & therapy
, 2021 (12), 240
Diabetic kidney disease alters the transcriptome and function of human adipose-derived mesenchymal stromal cells but maintains immunomodulatory and paracrine activities important for renal repair.
Hickson LJ, Eirin A, Conley SM, Taner T, Bian X, MBBCh AS, Herrmann SM, Mehta RA, McKenzie TJ, Kellogg TA, Kirkland JL, Tchkonia T, Saadiq IM, Tang H, Jordan KL, Zhu X, MBBCh MDG, Rule AD, van Wijnen AJ, Textor SC, Lerman LO
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The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the
External Evaluation Committee
The DiaComp Nephropathy Committee has the principal function of furthering the mission of the consortium with regard to diabetic kidney disease.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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