Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung

Abstract

Regenerative medicine was initially focused on tissue engineering to replace damaged tissues and organs with constructs derived from cells and biomaterials. More recently, this field of inquiry has expanded into exciting areas of translational medicine modulating the body's own endogenous processes, to prevent tissue damage in organs and to repair and regenerate these damaged tissues. This review will focus on recent insights derived from studies in which the manipulation of the innate immunologic system may diminish acute kidney injury and enhance renal repair and recovery without the progression to chronic kidney disease and renal failure. The manner in which these interventions may improve acute and chronic organ dysfunction, including the heart, brain, and lung, will also be reviewed.

Keywords: acute kidney injury; medical device; selective cytopheretic device; translational medicine.

Figure 1

Schematic representation of (a) selective cytopheretic device therapy (SCD_Rx) and (bi–iii) current understanding of the mechanism of action (MoA) of the SCD, which involves leukocyte (LE)/fiber interactions. (i) Binding of activated LE (purple) with mobilized surface integrins (green); (ii) “reset” LE; (iii) release of immunomodulated LE. Erythrocytes are depicted in all panels as red.

Figure 2

Micrographs of the sham, acellular cartridges as part of the regional citrate anticoagulation arm of the Renal Assist Device (RAD) clinical trial. Patient treatment demonstrated adherent leukocytes (LE) on the outer surface of the membranes of the cartridge along the blood flow path within the extracorporeal circuit, which translated into patient benefit. This was the basis for the treatment now referred to as SCD_Rx. (a–d) Light micrographs stained with hematoxylin and eosin. Low-power micrograph showing adherent cells around each fiber (a, original magnification ×160). (b,c) Higher-power micrographs showing clustering of bound LE (b and c, original magnification ×400). (d) High-power micrograph displaying predominance of NE and MO in the adherent cell clusters (original magnification ×1600). MO, monocyte; NE, neutrophil.

Figure 3

Human monocytes can be classified by CD14 and CD16 expression into classical (Q1: CD14⁺CD16⁻), intermediate (Q2: CD14⁺CD16⁺), and nonclassical (Q3: CD14^lowCD16⁺) subsets using flow-cytometric techniques. Representative cytometric analysis of systemic human blood is shown, with CD14 and CD16 expression displayed as a dot plot of relative fluorescence intensity (RFI). The intensity of CD11b expression of each event is heat mapped according to the arrow in Q4 (blue indicates lowest and red indicates highest CD11b RFI). The subsets have differential CD11b expression according to phenotype, contributing to integrin-dependent selective cytopheretic device selectivity for pro-inflammatory, classical, and intermediate MO. MO, monocytes.

Figure 4

(a,b) Area of the infarcted heart was evaluated using 2,3,5-triphenyltetrazolium chloride. Red indicates viable tissue; white (with corresponding outline trace) indicates irreversibly injured tissue. Uneven discoloration (darkening) of the hearts is due to residual Evans blue dye injected to identify the area at risk for infarct. Evaluation of all cross sections indicated that (b) selective cytopheretic device therapy (SCD_Rx) afforded a significantly reduced infarct size compared to (a) untreated controls (P < 0.05). For the chronic heart failure (CHF) model, ventriculograms of CHF canine heart: (c) baseline week 0 before SCD therapy (wk0 pre-Rx) and (d) week 4 after SCD therapy (wk4 post Rx). Red line depicts the border of the left ventricular diastolic silhouette (most relaxed state during filling); yellow line depicts the border of the left ventricular systolic image (most contracted state), demonstrating improved contractility (black arrows) of the left ventricle after SCD_Rx.

Figure 5

(a,b) Coronal brain sections are shown at the site of thrombin injection (arrows in a and b). Area of damage (demarcated by the dotted line) (a) can be identified by the lack of defined subcortical white matter due to swelling (edema) and is clearly evident in the (a) brain of the untreated control pig, but not in the (b) brain of a representative selective cytopheretic device therapy (SCD_Rx) animal. Bar = 1 cm. (c,d) Leukocytes (LE) normally not present in brain tissue migrate into sites of injury causing further damage. LE, identified by immunohistochemistry using a CD11R3-specific antibody (red), is more prevalent in the (c) untreated control animal, indicating that (d) SCD_Rx can limit damage from ICH. Nuclei of all cells are counterstained with DAPI (blue). Bar = 100 μm. SCD, selective cytopheretic device.