International Conference onStem Cells, Regenerative Medicine and Tissue Engineering

Title: Therapeutic Effects of Hydrogel-Formulated UC-MSCs Delivered Subcutaneously or via Perirenal Adipose Tissue (PRAT) in Murine Models of Lupus Nephritis and Obesity-Related Nephropathy

Abstract:

Objective: Human umbilical cord-derived Mesenchymal stem cells (UC-MSCs) exert their immunoregulatory effects by directly interacting with various innate and adaptive immune cells. Durable UC-MSC depots have been established via subcutaneous (SC) injection in proprietary hydrogel combinations as well as via administration into PRAT, which has been recently recognized as an important homeostatic organ regulating cardiovascular system and kidney maintenance via paracrine and endocrine mechanisms. The objectives of these studies were (a) to examine the therapeutic effects of hydrogel-formulated, clinical grade, human UC-MSCs administered via SC injection in a genetic MRL/lpr model of lupus and (b) to investigate the effects of intra-PRAT administration of these UC-MSCs in a High Fat Diet (HFD) obesity-related nephropathy model.
Methods: A. MRL/lpr model of lupus: On week 14 of the experiment, female MRL/lpr mice were injected with single SC UC-MSC injections formulated in two proprietary hyaluronic acid-based hydrogels. Mice were sacrificed at week 21 and serum, urine, and kidney samples were collected for analysis. B. Obesity-related nephropathy model of diabetic kidney disease: Male C57BL/6J mice were fed a high-fat diet (HFD; 60% fat, kcal) for 8 weeks. Age-matched male C57BL/6J mice were fed a standard laboratory normal diet (ND; 14% fat, kcal) as a control group. At week 8, UC-MSCs were injected in two doses into the right PRAT. The mice continued on HFD/ND for another 6 weeks. Mice were sacrificed at week 14 and kidney and PRAT samples were collected for analysis.  
Results: A. SC administration of hydrogel-formulated UC-MSC in the lupus model triggered a reduction in the relative expression of both pro-inflammatory markers (TNFα, IL1β, IL6, IL18a, C-C Chemokine 2 (CCL2)) and pro-fibrotic markers (Fibronectin-1 (FN1), Collagen 1A1 (COL1A), TGFβ) in the kidneys. B. Administration of UC-MSC intra-PRAT in the HFD model induced systemic effects, including reduction in blood glucose, urine creatine, and urine urea concentrations, as well as lowering of urine Neutrophil gelatinase-associated lipocalin (NGAL) levels, a significant biomarker for kidney injury in kidney disease and lupus nephritis. Furthermore, UC-MSC administration intra-PRAT initiated a reduction in the relative expression of pro-inflammatory markers (IL6, TNFα, CCL2, and Connexin 43 (Cx43)) as well as pro-fibrotic markers (FN1 and Col1A1) in the kidneys. In the PRAT itself, administration of UC-MSC triggered a reduction in the relative expression of IL1β and CCL2 as well as a sharp reduction in the relative expression of KIM1, a transmembrane glycoprotein which is recognized as an early, sensitive, and specific biomarker for kidney injury.
Conclusions: By employing UC-MSC, via SC or intra-PRAT routes of administration, both systemic and molecular-level beneficial effects were observed in models of lupus and diabetic kidney disease. It is hypothesized that UC-MSCs exert their anti-inflammatory and anti-fibrotic effects by releasing EVs and soluble active molecules in a paracrine fashion. These results support UC-MSCs’ immunomodulatory activity and form the basis for our ongoing Ph1/2a clinical study in lupus.   

Biography:

Dr. Alon Yaar: Founder and former CEO at NeuroDerm (CNS pharma company), a unikorn bought by Mitsubishi Tanabe Pharma in 2017 for more than 1B$. Alon is a healthcare professional executive and serial entrepreneur with more than 25 years in the pharma and biotech industry. Dr. Yaar is an expert in developing novel therapies to make key, transformational, and effective changes in patient’s lives. Alon is working now on his next medical breakthrough startup - LiveKidney, which promises to delay the need for kidney transplantation or dialysis, using UC-MSCs technology.