Intralesional Infiltrations of Arteriosclerotic Tissue Cells-Free Filtrate Reproduce Vascular Pathology in Healthy Recipient Rats

Abstract

Lower-extremity arterial disease is a major health problem with increasing prevalence, often leading to non-traumatic amputation, disability and mortality. The molecular mechanisms underpinning abnormal vascular wall remodeling are not fully understood. We hypothesized on the existence of a vascular tissue memory that may be transmitted through soluble signaling messengers, transferred from humans to healthy recipient animals, and consequently drive the recapitulation of arterial wall thickening and other vascular pathologies. We examined the effects of the intralesional infiltration for 6 days of arteriosclerotic popliteal artery-derived homogenates (100 µg of protein) into rats’ full-thickness wounds granulation tissue. Animals infiltrated with normal saline solution or healthy brachial arterial tissue homogenate obtained from traumatic amputation served as controls. The significant thickening of arteriolar walls was the constant outcome in two independent experiments for animals receiving arteriosclerotic tissue homogenates. This material induced other vascular morphological changes including an endothelial cell phenotypic reprogramming that mirrored the donor’s vascular histopathology. The immunohistochemical expression pattern of relevant vascular markers appeared to match between the human tissue and the corresponding recipient rats. These changes occurred within days of administration, and with no cross-species limitation. The identification of these “vascular disease drivers” may pave novel research avenues for atherosclerosis pathobiology.

Cell-Free Filtrates (CFF) as Vectors of a Transmissible Pathologic Tissue Memory Code: A Hypothetical and Narrative Review

“…The so-called “aberrant angiogenesis” was also observed, in which muscle myofibrils are replaced by vascular-like channels that may contain an endothelial collar, so that one tissue lineage is substituted by an unrelated one (not shown) [ 48 ]. Furthermore, as described for the diabetes study, immunohistochemistry experiments confirmed that the arteriosclerotic material recipient rats entirely recreated the immunoexpression pattern of vascular critical markers found in the pathologic donor samples [ 46 ].…”

“…It was evidenced that non-diabetic diseased arteries include a surge of “priming factors” that appear to be soluble, can be transferred, and impose the “damage phenotype” in naïve recipient tissues [ 37 ]. Accordingly, and in terms of diabetes, we deem that these “vascular memory factors” are circulating messengers that may contribute to arterial disease debut, perpetuation, dissemination, and irreversibility [ 46 ].…”

“…It was again observed that in a 7-day administration period, the human arteriosclerotic-derived filtrate induced the recapitulation of angiogenic and arterial anomalies within the host rat-granulation tissue. Interestingly, these rats reproduced the donor’s occlusion pattern characterized by the projection and luminal encroachment of collagen bundles and the presence of fusiform, fibroblast-like cells, apparently replacing endothelial cells [ 46 ]. This observation may represent an endothelial-to-mesenchyme reprogramming process [ 47 ] ( Figure 2 ).…”

Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice

“…The experimental methodology used in this opportunity was as previously described ( Berlanga-Acosta et al, 2022c ); tumor-derived CFFs were prepared using a sterile physiologic saline solution with no purification processes or any other type of chemical manipulation. These CFFs are homogenates that represent a pure extract of the pathologic tissues, are rich in content material, and are a vehicle of donor cell soluble signatures that have previously been proven to recapitulate in healthy recipient rodents the histopathologic hallmarks of diabetic angiopathy and neuropathy and non-diabetic-related arteriosclerosis as models of non-communicable chronic diseases ( Berlanga-Acosta et al, 2021 ; Berlanga-Acosta et al, 2022b ). Of note, we described that despite the mechanical processing of tissue disruption to elaborate the CFFs, molecules of DNA and RNA from the tumors are detected in the homogenates, and RNA may be successfully reverse-transcribed and its product amplified.…”

Carcinogenic Effect of Human Tumors-Derived Cell Free-Filtrates in Nude Mice

“…We recently undertook the use of cells-free filtrates (CFFs) derived from fresh human pathologic tissue samples, to examine the hypothesis that the "chemical codes" of non-communicable diseases are imprinted in target tissues, that could be extracted, passively transferred to healthy animals, and accordingly reproduce the histological hallmarks of the human donor [22]. These experiments demonstrated that CFFs acted as a vehicle for delivering the soluble signalers that imposed the pathologic donors' phenotypes in otherwise normal animals [23,24]. Subsequently and following the hypothesis that CFFs may contain cell-transforming messengers, we examined the consequences on nude mice of administering the homogenates of surgically excised malignant tumors.…”