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Abstract
Mesangial injury produced by glomerulopathic monoclonal immunoglobulin light chains leads to two diametrically opposed results: matrix loss from mesangiolysis / replacement of mesangial matrix with amyloid (AL-amyloidosis) and increased matrix (light chain deposition disease), depending on the physicochemically abnormal light chains involved. In both situations; however, there is loss of mesangial cells resulting from apoptosis induced by the glomerulopathic light chains. This unique experimental model of mesangial injury resulting in divergent manifestations allows examining the role of mesenchymal stem cells in mesangial glomerular repair in the two typical prototypes of alterations that occur in the mesangium when injured by a variety of injurious agents. In vitro and ex vivo platforms are used to translate information from the in-vitro to the in-vivo arenas. Both platforms highlight the same sequence of events that take place: mesenchymal stem cells identify the site of damage, clear the damaged mesangium by eliminating debris from apoptotic cellular elements and deposited “foreign” (not belonging in the normal mesangium) material and eventually differentiate into mature mesangial cells laying down new matrix. Each of the platforms employed exhibited certain advantages and limitations in visualizing and understanding the processes that occur. When the information generated was combined, a clear view of mechanisms involved and how mesenchymal stem cells participated in mesangial repair emerged.
Highlights
Some glomerular diseases center their pathologic manifestations in the mesangium, either in their initial phases or as they evolve into chronicity, where progressive damage results in irreversible events leading to glomerulosclerosis
Diseases with mesangiocentric pathology include nodular diabetic glomerulosclerosis, the most common glomerulopathy associated with a systemic disorder which is characterized by excess production of mesangial matrix by mesangial cells (MCs) via activation of transforming growth factor-β [5], reproducing the pathology seen in light chain deposition disease (LCDD) and thrombotic microangiopathy where mesangiolysis resulting from activation of metalloproteinases is a key pathologic event similar to what occurs in AL amyloidosis [6]
Expression of caspase 3 (Figure 1A), and the release of apoptotic bodies extruded from the cells (Figure 1B) confirmed activation of the apoptotic pathways in the MCs incubated with GLCs
Summary
Some glomerular diseases center their pathologic manifestations in the mesangium, either in their initial phases or as they evolve into chronicity, where progressive damage results in irreversible events leading to glomerulosclerosis. This is the case with glomerulopathic light chains (LCs) which because of their peculiar physicochemical composition and conformation are able to interact with receptors located at the cellular membranes of mesangial cells (MCs) and produce pathological alterations [1,2,3,4]. While controlling the injurious agent is crucial to avoid repetitive and/or continuous renal damage, once damage has occurred, fixing the mesangial alterations becomes important to improve renal function and avoid the inevitable progressive damage that results in end-stage renal disease, requiring dialysis or transplantation with their expected management challenges and complications
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